TOXICOLOGICAL PROFILE FOR PENTACHLOROPHENOL Prepared by: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry May 1994 PENTACHLOROPHENOL ii DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. PENTACHLOROPHENOL iii UPDATE STATEMENT A Toxicological Profile for pentachlorophenol was released on December 1989. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry { (0.09 ppm) (ACGIH 1990). Occupationally exposed workers at a wood-treatment plant exhibited a statistically significant increase in low-grade inflammation of skin and subcutaneous tissue, conjunctival membrane of the eyes, and severe eruptions of the skin. However, it is possible these symptoms resulted from exposure to contaminants in pentachlorophenol (chlorinated dibenzo-p-dioxins, dibenzofurans) and other materials such as dieldrin and chromium, fluorine, arsenic, copper, boron, and tin compounds (Baader and Bauer 1951; Klemmer et al. 1980). In another investigation, intermediate (3-month) inhalation exposure to sodium pentachloro- phenate vapors during its manufacture resulted in chloracne characterized by extensive cysts and pus-forming abscesses prominently over the face, chest, abdomen, and proximal part of the extremities (Seghal and Ghorpade 1983). Exposure concentration and purity of sodium pentachlorophenate were not specified, but it is possible that the chloracne was a result of chlorinated dibenzo-p-dioxin and dibenzofuran contaminants present in technical grade and/or inhalation of fumes during the bubbling of chlorine through phenol. Chloracne (incidence determined by company medical records) was also reported in 47 of 648 (7%) pentachlorophenol production workers exposed for an average of 1.4 years (O'Malley et al. 1990). There was no relationship between length of employment in the pentachlorophenol department and risk of chloracne. Pentachlorophenol produced in this plant was contaminated with hexachlorinated dibenzo-p-dioxins (HxCDD), heptachlorinated dibenzo-p-dioxins (HpCDD), and octachlorinated dibenzo-p-dioxins (OCDD) and dibenzofurans, all substances known to cause chloracne. There are no documented cases of chloracne associated with exposure to pure pentachlorophenol. Hosenfeld et al. (1986) reported the presence of skin abnormalities (type not specified) in some residents of log homes treated with pentachlorophenol. PENTACHLOROPHENOL 15 2. HEALTH EFFECTS Other Systemic Effects. A brief report provided evidence that prolonged exposure to commercial pentachlorophenol-containing wood preservatives may be associated with reproductive disorders that are secondary to endocrine and immunological dysfunction (see Sections 2.2.1.3 and 2.2.1.5) (Gerhard et al. 1991). Twenty-two of 90 women with histories of habitual abortion, unexplained infertility, menstrual disorders, or the onset of menopause were examined and found to have elevated blood levels of pentachlorophenol (>25 pg/L) and/or lindane (>100 ng/L). Exposure duration was 4.6-10 years, and exposure occurred via offgassing (from wooden ceiling and wall panels and from carpets and leather upholstery treated with wood preservatives) as well as via dermal contact with these treated materials. Pentachlorophenol blood levels were highest in the women with infertility (mean = 73 pg/L) and lower in those with menstrual dysfunction (42 pg/L). Seventeen of the 22 women also exhibited adrenocortical insufficiency, and 6 of these women had thyroid dysfunction (no further details provided). Because lindane was also present in the blood of these women, a direct causal relationship with pentachlorophenol alone cannot be concluded. Furthermore, given the sparse reporting of details, other confounding factors cannot be eliminated. 2.2.1.3 Immunological Effects A brief report provided evidence that prolonged exposure to commercial pentachlorophenol- containing wood preservatives may be associated with reproductive disorders that are secondary to immunologic and endocrine dysfunction (for details, see Section 2.2.1.2, Other Systemic Effects; see also Section 2.2.1.5) (Gerhard et al. 1991). Fifteen of the 22 women with reproductive disorders were found to have "immunological disorders" (no further details were given). No studies were located regarding immunological effects in animals after inhalation exposure to pentachlorophenol. 2.2.1.4 Neurological Effects There have been no indications that inhalation exposure to pentachlorophenol causes adverse ctfects on the central or peripheral nervous systems in humans. Chronic exposure to pentachloro- phenol vapors (0.0003-0.18 mg/m?) at a chemical plant resulted in no detectable neurophysiologi- cal effects in exposed workers. Air samples also contained tetrachlorophenols (0.291 mg/m’), and PENTACHLOROPHENOL 16 2. HEALTH EFFECTS aldrin and lindane (<5 mg/m?), so inhalation exposure was not limited to pentachlorophenol (Triebig et al. 1987). No studies were located regarding neurological effects in animals following inhalation exposure to pentachlorophenol. 2.2.1.5 Reproductive Effects A brief report provided evidence that prolonged exposure to commercial pentachlorophenol- containing wood preservatives may be associated with reproductive disorders that are secondary to endocrine and/or immunologic dysfunction (for details, see Section 2.2.1.2, Other Systemic Effects; see also Section 2.2.1.3) (Gerhard et al. 1991). Twenty-two of 90 women with histories of habitual abortion, unexplained infertility, menstrual disorders, or onset of menopause were examined and found to have elevated blood levels of pentachlorophenol (>25 pg/L) and/or lindane (>100 ng/L). No studies were located regarding reproductive effects in animals following inhalation exposure to pentachlorophenol. 2.2.1.6 Developmental Effects No studies were located regarding developmental effects in humans or animals after inhalation exposure to pentachlorophenol. 2.2.1.7 Genotoxic Effects Occupational exposure to pentachlorophenol at concentrations that ranged from 1.2 to 180 pgm’ for 3-34 years did not result in any increased incidence of sister chromatid exchanges or chromosomal aberrations in 20 exposed workers (Ziemsen et al. 1987). A statistically significant increase in the frequency of chromosomal aberrations was observed in peripheral lymphocytes of workers exposed to pentachlorophenol primarily by inhalation in a manufacturing plant; the frequency of sister chromatid exchanges was not increased (Bauchinger et al. 1982). No increase in the frequency of chromosome aberrations was observed in a second study of workers PENTACHLOROPHENOL 17 2. HEALTH EFFECTS exposed in a wood-treatment plant; however, this result is not conclusive because of the small number of subjects and lymphocytes examined in this study (Wyllie et al. 1975). No studies were located regarding genotoxic effects in animals after inhalation exposure to penta- chlorophenol. Other genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer Case reports suggest a possible association between cancer (Hodgkin's disease, soft tissue sarcoma, and acute leukemia) and occupational exposure to technical pentachlorophenol (Fingerhut et al. 1984; Greene et al. 1978; Roberts 1983). These studies are limited by confounding factors such as concurrent exposure to other potentially carcinogenic chemicals, small sample size, follow-up periods too short to detect an excess cancer risk, mortality due to competing causes of death, and brief exposure periods. There is no convincing evidence from epidemiological studies to indicate that inhalation of pentachlorophenol in any form produces cancer in humans (Gilbert et al. 1990; Jéippinen et al. 1989; Robinson et al. 1985). For example, workers exposed to wood treating chemicals between the years of 1960 and 1981 were evaluated for health-related problems. Eighty-eight wood treaters having exposures of 0.33-26.3 years, with a median of 6.5 years, were compared to 58 matched controls. The study detected no adverse health effects or increased incidence of mortality from exposure even though the urinary pentachlorophenol excretion levels were clearly increased (174 ppb versus 35 ppb) (Gilbert et al. 1990). No studies were located regarding cancer in animals after inhalation exposure to pentachloro- phenol. 2.2.2 Oral Exposure Only one report was found in the literature concerning adverse effects in humans of ingestion of pentachlorophenol (Haley 1977). However, pentachlorophenol (particularly the technical grade) has been shown to affect several organ systems in experimental animals. Major target organs or PENTACHLOROPHENOL 18 2. HEALTH EFFECTS systems of pentachlorophenol-induced toxicity in experimental animals include liver, kidney, central nervous system, and immune system. Hematologic and cardiovascular effects have also been noted following oral administration of pentachlorophenol in experimental animals. Many of these effects are most likely the result of uncoupling of oxidative phosphorylation (see Section 2.4) which leads to hyperthermia and related effects, or the result of chlorinated dibenzo- p-dioxin impurities in technical grade pentachlorophenol. 2.2.2.1 Death One case report was found in the reviewed literature that described a suicide from pentachloro- phenol ingestion, but the amount of pentachlorophenol ingested was not specified (Cretney 1976). The lowest human lethal dose for pentachlorophenol is estimated to be 1 gram (approximately 17.0 mg/kg) (Driesbach 1980). Pentachlorophenol may cause death in experimental animals following ingestion. Death usually is a result of hyperthermia. There does not appear to be much difference in doses that cause death across species. Preweaned and adult rats have been reported to have lower oral LDsgs for penta- chlorophenol than juvenile rats (25-50 days old) (St. Omer and Gadusek 1987). Toxicity of pentachlorophenol was greatly enhanced when it was administered in a fuel oil or corn oil vehicle (see Table 2-1). Absorption of chemicals such as pentachlorophenol that have substantial lipid solubility across skin and mucous membranes is increased by the presence of hydrocarbon or corn oil solvents. The greater toxicity of pentachlorophenol when dissolved in these vehicles may be due partly or entirely to more efficient absorption of pure pentachlorophenol. All reliable LDDs values for death in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.2 Systemic Effects No studies were located regarding respiratory, gastrointestinal, or musculoskeletal effects in humans or animals after oral exposure to pentachlorophenol. The cardiovascular, hematological, hepatic, renal, and dermal/ocular effects observed after oral exposure to pentachlorophenol are discussed below. PENTACHLOROPHENOL 19 2. HEALTH EFFECTS The highest NOAEL values and all reliable LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Cardiovascular Effects. One report describing effects of ingestion of pentachlorophenol in humans was found in the literature (Haley 1977). In this case, an adult male intentionally ingested an estimated 4-8 ounces of weed killer that contained 12% pentachlorophenol, 1.5% other chlorinated phenols, 82% aromatic hydrocarbons, and 4.5% inert ingredients. Clinical signs observed upon subsequent hospital admission included tachycardia. This effect is most likely the result of pentachlorophenol’s ability to uncouple oxidative phosphorylation, leading to hyperthermia. One early report described the occurrence of extensive vascular damage and heart failure in rats, rabbits, guinea pigs, and dogs following a single oral administration (dose not specified) of penta- chlorophenol of unidentified purity (Deichmann et al. 1942). Hematological Effects. No studies were located regarding hematological effects in humans after oral exposure to pentachlorophenol. Various changes of questionable biological significance have been reported in animal studies. These effects were seen following exposure to technical pentachlorophenol but not purified pentachlorophenol. A depression in number of erythrocytes, a decrease in hemoglobin level, and a decrease in packed cell volume were observed in rats fed technical pentachlorophenol for 90 days but not in those fed purified pentachlorophenol (Johnson et al. 1973). However, a decrease in white blood cell count was observed in pigs administered purified pentachlorophenol for 30 days (Greichus et al. 1979). Conflicting findings were reported in rats fed pentachloro- phenol of unidentified purity for 12 weeks (Knudsen et al. 1974). Increased hemoglobin and hematocrit were observed after 6 weeks of treatment, followed by a decrease in hemoglobin and erythrocytes at study termination. These findings collectively indicate that impurities present in technical grade pentachlorophenol may be the cause of the hematologic effects described above. Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to pentachlorophenol. TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form ACUTE EXPOSURE Death 1 Rat (GW) Once 211 (LDgq) Deichmann et al. 2% NaPCP 1942 in water 2 Rat (GO) Once 78 (LDgp) Deichmann et al. 1% tech 1942 in olive oil 3 Rat (GW) Once 50 (LDgg) St. Omer and tech Gadusek 1987 4 Rat (GO) Once 27 (LDgp) Deichmann et al. 0.5% tech 1942 in fuel oil 5 Mouse (GO) Once 129 (LDgo[M1) Renner et al. pure 134 (LDgo[F1) 1986 6 Mouse (G) Once 177 (LDgo[M1) Borzelleca et pure 117 (LDgo[F1) al. 1985 Immunological 7 Mouse (GO) 14 d 100 White and pure 7d/wk Anderson 1985 8 Mouse (GO) Once 15 30 (decreased IgM Kerkvliet et al. tech antibody 1985a response) 9 Mouse (GO) Once 120 Kerkvliet et al. pure 1985a 10 Mouse (GO) 14d 100 Holsapple et al. EC-7 7d/wk 1987 " Mouse (GO) 14d 100 (inhibition of White and tech 7d/wk complement Anderson 1985 activity) S103443 HITV3H 2 TON3IHdOHOTHOV.LN3d oc TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure” Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 12 Mouse (GO) 14d 10 (decreased IgM Holsapple et al. tech 7d/wk antibody 1987 response) Developmental 13 Rat (Go) 10d 5 15 (lumbar spurs) 30 (skeletal Schwetz et al. tech Gdé-15 anomalies; 1974 17% decreased fetal body weight) 14 Rat (Go) 10d 5° (delayed ossifi- 15 (skeletal Schwetz et al. pure Gd6-15 cation of skull anomalies) 1974 bones) 30 (42% decreased fetal body weight) Reproductive 15 Rat (Go) 10d 5 13 (increased Schwetz et al. tech Gdé-15 resorptions) 1974 16 Rat (Go) 10d 5 30 (increased Schwetz et al. pure Gd6-15 1974 resorptions) S103443 H1TV3H 2 JON3IHdJOHOTHOV.IN3d 12 TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form INTERMEDIATE EXPOSURE Death 17 Rat (GW) 1-3 mo 300 (LDsq) Nishimura et al. tech 2x/wk 1980 Systemic 18 Rat (F) 8 mo Hepatic 1 5 (fibrosis; Kimbrough and tech 7d/wk enlarged pleio- Linder 1978 morphic hepato- cytes; vacuo- lization; hyper- plasia; porphyria; pigmented Kupffer cells) Renal 25 Other 25 (15-16% decreased body weight) 19 Rat (F) 8 mo Hepatic 5 25 (slightly enlarged Kimbrough and pure 7d/wk hepatocytes) Linder 1978 Renal 25 Other 25 ([M1: 10% decreased body weight) 20 Rat (GW) 1-3 mo Hepatic 40 (increased liver Nishimura et al. tech 2x/wk weight; decreased 1980 hepatic glycogen; increased serum lactate dehy- drogenase, SGOT and SGPT; hepato- cellular swelling; vacuolization) Other 40 (increased blood glucose) S103443 H1TV3H 2 TON3HdJOHOTHOV.LN3d 22 TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 21 Rat (F) 12 wk Hemato 1.2 2.5 (increased and Knudsen et al. tech 7d/wk decreased hemo- 1974 globin and red blood cell count) Hepatic 1.2° (increased alkaline phosphatase; increased SGPT) Renal 2.5 22 Rat (F) 181d Other 4 43 (15% decreased Welsh et al. pure 7d/wk maternal body 1987 weight) 23 Mouse (F) 10-12 wk Hepatic 6.5 (hepatocellular Kerkvliet et al. pure 7d/wk swelling; vacuo- 1982 lization; multi- focal necrosis) 24 Mouse (F) 10-12 wk Hepatic 6.5 (hepatocyte Kerkvliet et al. tech 7d/wk swelling; vacuoli- 1982 zation; multifocal necrosis) 25 Pig (cy 30d Hemato 5 10 (decreased white Greichus et al. pure 7d/wk blood cell count) 1979 Hepatic 5 10 (increased liver weight; diffuse cloudy hepato- cellular swelling) Renal 10 Immunological 26 Mouse (F) 6 wk 0.5 (decreased anti- Kerkvliet et al. tech 7d/wk body response) 1985a 27 Mouse (F) 10-12 wk 6.5 (enhanced suscep- Kerkvliet et al. tech 7d/wk tibility to tumor 1982 growth) S103443 H1TV3H 2 TON3IHdJOHOTHOVIN3d £2 TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 28 Mouse (F) 10-12 wk 65 (enhanced suscep- Kerkvliet et al. pure 7d/wk tibility to tumor 1982 growth) 29 Mouse (F) 8 wk 12.5 (reduction in Kerkvliet et al. tech 7d/wk lymphoprolifer- 1985b ative response in mixed lympho- cyte culture) Neurological 30 Rat (W) 3-14 wk 1 (increased acid Savolainen and tech 7d/wk proteinase and Pekari 1979 superoxide dis- mutase, decreased cerebral diaphor- ase activity in brain; decreased glial gluta- thione concen- tration) Developmental 3 Rat (F) 181d 4 13 (M1: 10% 43 (embryo lethality) Welsh et al. pure 7d/wk decreased fetal 1987 body weight) 32 Rat (F) 2 gen 25 (decreased litter Exon and Koller tech 7d/wk size) 1982 S103443 HLTV3H 2 TON3IHdJOHOTHOVY.LN3d ve TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) Key to figure® Species Exposure duration/ Route frequency System LOAEL (effect) NOAEL Less serious Serious (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form CHRONIC EXPOSURE Systemic 33 Rat (F) 22-24 mo Hepatic 7d/wk Renal Other 3[F] 10 (accumulation of Schwetz et al. brown pigment 1978 [identity not specified]; elevated SGPT) 3[F] 10 (accumulation of 10 [M] brown pigment in kidney tubules [identity not specified]; increased urine specific gravity) 10[F] 30 (LF): 12% decreased 30M] body weight as compared to controls) EC-7 S103443 HITV3H 2 TON3IHJOHOTHOV.LN3d Se TABLE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form Cancer 34 Mouse (F) 103 wk 17.5 (pheochromocy- NTP 1989 EC-7 1x/d tomas; hepato- cellular carci- noma-CEL) 35 Mouse (F) 103 wk 18 (hemangiosarcomas NTP 1989 TG-penta 1x/d of the liver and spleen-CEL .The number corresponds to entries in Figure 2-1. Used to derive an acute oral Minimal Risk Level (MRL) of 0.005 mg/kg/day; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). ‘Used to derive an intermediate oral Minimal Risk Level (MRL) of 0.001 mg/kg/day; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). (C) (F) capsule; CEL = cancer effect level; d = day(s); Derm/oc = dermal/ocular; EC-7 = a mixture containing 90% pure pentachlorophenol; feed; [F] = female(s); (G) = gavage; Gd = gestation day; gen = generation(s); (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; IgM = immunoglobulin M; LOAEL = lowest-observed-adverse-effect level; LD;, = lethal dose, 50% kill; [M] = males; mo = month(s); NaPCP = sodium pentachlorophenol; NOAEL = no-observed-adverse-effect level; SGOT = serum glutamic oxaloacetic transferase; SGPT = serum glutamic pyruvic transaminase; tech = technical grade; TG-penta = technical grade pentachlorophenol; (W) = water; wk = week(s); x = time(s) S103433 HLOV3IH 2 TON3IHdJOHOTHOV.IN3d 9c FIGURE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral ACUTE (<14 Days) » & © 0 F & # > © &* & &* & (mg/kg/day) 1,000 = Bo 100 Mi sm Eom 2 Om Om Oiom Ptim k ar Qi @« @ 6 B 4r @em 8m Dir @14r @ 5 10 12m Om Qrar O1sr Oter 1 1 1 ¥ 1 1 1 1 +5 HE oo 1 1 1 I 1 0.01 | ' 1 / 0.001 - Key r Rat . m Mouse - LDso 1 Minimal risk level for Pig LOAEL for serious effects (animals) 1 effects other thar Cancer LOAEL for less serious effects (animals) i QO NOAEL (animals) Set @ CEL-Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 2 JON3HJOHOTHOVINId 22 FIGURE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (continued) (mg/kg/day) 1,000 100 10 0.1 0.01 0.001 INTERMEDIATE (15-364 Days) Systemic N » & © F ; & & $$ © s & & & 3 & ng & 3 & & S&F Ff 3° F & Ff J € Ff " 17r 28m @20r Oror @22r Poor @sir Dor Orer rer Por @32 Das Ds onl eso Ozsp Po O2sp 3m 24m 190 @ rer Oz2sp Ozer m Ostr Qa Oar Oar Over Parr sor : 26m I 1 1 1 1 1 1 I 1 hd Key r Rat * m Mouse “ LDso I Minimal risk level for Pig LOAEL for serious effects (animals) 1 oHocts other than cancer Pp o LOAEL for less serious effects (animals) 1 O NOAEL (animals) ~ @ CEL-Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1IV3H 2 TONIHJOHOTHOVIN3d 82 FIGURE 2-1. Levels of Significant Exposure to Pentachlorophenol - Oral (mg/kg/day) 100 10 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 CHRONIC (> 365 Days) Systemic (continued) NOAEL (animals) © $ & > & & RK S *® & J & - a3 33r @®34m @asm 33r 33r 104 10-5 | Estimated Upper- Bound Human Cancer Risk 106 Levels 10-7 Key r Rat B LD50 . B } m Mouse @ LOAEL for serious effects (animals) i Wimslsish levels p Pig ; I effects other than cancer @ LOAEL for less serious effects (animals) 1 Oo r ¢ CEL-Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 2 JON3HdJOHOTHOV.IN3d 62 PENTACHLOROPHENOL 30 2. HEALTH EFFECTS The liver appears to be a target organ for pentachlorophenol-induced toxicity in experimental animals. Single exposures to pentachlorophenol by gavage at doses greater than 10 mg/kg induced an increase in relative liver weight, as well as hepatic glycogen (10 times control levels) and lactate in rats (Nishimura et al. 1982). Evidence of biochemical (i.e., alterations in hepatic enzyme activities and porphyria), functional (i.e, changes in liver glycogen levels), and gross and histopathological (e.g., increase in relative liver weight, hyperplasia, fibrosis, hepatocellular enlargement and vacuolization, and degeneration) effects is seen following intermediate and chronic oral exposure to pentachlorophenol in rodents. The majority of hepatotoxic effects of pentachlorophenol appear to be related to the level of impurities in the technical product (e.g., polychlorinated dibenzo-p-dioxins and dibenzofurans) rather than the purified chemical. Studies that compared effects of technical to pure pentachloro- phenol will be reviewed in an attempt to determine the hepatotoxic effects of pure pentachloro- phenol. Dietary technical grade pentachlorophenol (3-30 mg/kg/day) induced increased liver weight, minimal focal hepatocellular degeneration, and necrosis in rats exposed for 90 days (Johnson et al. 1973). Purified pentachlorophenol at the same doses was reported to result only in increased liver weight at the highest dose without accompanying histopathologic changes. Technical grade pentachlorophenol incorporated into the diet of rats at doses of 1-25 mg/kg/day for 8 months induced fibrosis, enlarged pleomorphic hepatocytes, vacuolization, hyperplasia, and porphyria. In contrast, purified pentachlorophenol by the same regimen resulted only in slightly enlarged hepatocytes and pigmented Kupffer cells (Kimbrough and Linder 1978). Biochemical changes in the liver also seem to result from impurities in technical grade penta- chlorophenol. For example, in rats exposed to technical grade pentachlorophenol in their diet at doses of 1-25 mg/kg/day for 8 months, increases in liver weight, hepatic microsomal enzyme activity, and microsomal heme as well as porphyria were observed. Animals exposed to the same doses of purified pentachlorophenol exhibited only increased glucuronyl transferase activity (Kimbrough and Linder 1978). In a study that was conducted in rats using a preparation contaminated with OCDD, hepatic effects similar to those seen with technical grade pentachloro- phenol were reported (Knudsen et al. 1974). These effects included increased liver weight, PENTACHLOROPHENOL 31 2. HEALTH EFFECTS increased activity of liver enzymes, and centrilobular vacuolization, and they were observed at lower doses than those reported above (1.25-10 mg/kg/day). Based on a LOAEL of 1.2 mg/kg/day for liver effects in this study, an intermediate oral MRL of 0.001 mg/kg/day was calculated, as described in the footnote in Table 2-1. Purified pentachlorophenol appears to exhibit some degree of liver toxicity. Dowicide EC-7, a preparation of 90% pure pentachlorophenol that contains lower levels of those impurities implicated as the active toxic agent of technical preparations (chlorinated dibenzo-p-dioxins and dibenzofurans, see Table 2-2), induced significantly elevated serum glutamic pyruvic transaminase (SGPT) levels, darkly discolored livers, and brown pigment in the hepatocytes (mostly in females) in rats fed 30 mg/kg/day for 24 months (Schwetz et al. 1978). Nonspecific diffuse cloudy hepatocellular swelling, characterized by enlarged cells with finely vacuolated cytoplasm, was observed in young pigs given capsules that contained 5-15 mg/kg/day of purified pentachloro- phenol (Greichus et al. 1979). Hepatic effects were also observed in rats given 90% pure penta- chlorophenol by gavage at doses of 40-160 mg/kg/day (Nishimura et al. 1980). These investigators reported significant increases in liver weight accompanied by increases in serum lactate dehydrogenase (LDH), SGPT, and SGOT levels, and hepatocellular swelling and vacuolization at the lowest dose tested. Similarly, no difference was observed in the dose-dependent increase in severity of liver lesions (which consisted of hepatocellular swelling, vacuolization, and mild-to- moderate multifocal necrosis) exhibited by mice treated with the same doses of technical and purified pentachlorophenol for 10-12 weeks (Kerkvliet et al. 1982). The National Toxicology Program (NTP 1989) conducted 30-day and 6-month dietary range- finding studies with three different preparations of pentachlorophenol (technical grade, Dowicide EC-7, or pure) in B6C3F| mice (see Table 2-2). Diffuse centrilobular cytomegaly, karyomegaly, nuclear atypia, degeneration, or necrosis were seen in livers of mice treated with all grades at doses at or above 500 ppm for 30 days. Similar histopathologic changes were observed with all preparations in the 6-month study at doses at or above 200 ppm, and these were accompanied by increases in serum levels of enzymes associated with hepatic injury, a dose-related induction of aryl hydrocarbon hydroxylase, and an increase in cytochrome P-450 (NTP 1989). Renal Effects. No studies were located regarding renal effects in humans after oral exposure to pentachlorophenol. Table 2-2. Results of Analyses of Impurities Present in the Pentachlorophenol Used in NTP Feeding Studies and the Types of Tumors They Induce®® Dowicide Tumor Impurity Technical grade EC-T° Pure type Species Dichlorophenol -- -- - No data Trichlorophenol® 100 ppm 70 ppm 100 ppm Liver, leukemias®, Rat, mouse lymphomas Tetrachlorophenol 38,000 ppm 94,000 ppm 14,000 ppm Not carcinogenic Rat, mouse Hexachlorobenzene 50 ppm 65 ppm 10 ppm Liver Rat, hamster, mouse Thyroid /parathyroid Rat Adrenal Rat Kidney Rat Lymphosarcomas Mouse Tetrachlorodibenzodioxin -- <0.04 ppm <0.08 ppm Liver, thyroid Rat, mouse (both tumor types) Hexachlorodibenzodioxin 10.1 ppm 0.19 ppm <1 ppm Liver Rat, mouse Heptachlorodibenzodioxin 296 ppm 0.53 ppm -- No data Octachlorodibenzodioxin 1,386 ppm 0.69 ppm <1 ppm No data Pentachlorodibenzofuran 1.4 ppm -- -- No data Hexachlorodibenzofuran 9.9 ppm 0.13 ppm -- No data Heptachlorodibenzofuran 88 ppm 0.15 ppm - No data Octachlorodibenzofuran 43 ppm -- = No data Heptachlorohydroxydiphenyl ether 500 ppm’ -- 100 ppm No data Octachlorohydroxydiphenyl ether 19,100 ppm - 900 ppm No data S103443 H1IVAH 2 JONIHJOHOTHOV.INId 2g Table 2-2. Results of Analyses of Impurities Present in the Pentachlorophenol Used in NTP Feeding Studies and the Types of Tumors they Induce®®(continued) Dowicide Tumor Impurity Technical grade EC-7° Pure type Species Nonachlorohydroxydiphenyl ether 35,600 ppm -- 2,100 ppm No data Hexachlorohydroxydibenzofuran 1,600 ppm -- 1,100 ppm No data Heptachlorohydroxydibenzofuran 4,700 ppm - 2,200 ppm No data Samples were dissolved in benzene, placed on a deactivated alumina column, and eluted with benzene. Further separation was carried out with a basic aluminum oxide column; elution was with methylene chloride in hexane. Identification was performed by gas chromatography with an SP2100 capillary column/mass spectrometry; quantitation was by comparison with spiked samples analyzed by gas chromatography with an SP1240 DA column. ®Derived from: NTP 1989 ‘Four unidentified impurities with concentrations of 0.14, 0.057, 0.045, and 0.035 ppm were also detected. identified as the 2,3,6-isomer; another isomer was believed to be present but was not identified. Data are for 2,4,6-isomer. {Includes octachlorodiphenyl ether -- = not detected; EC-7 = Dow Company chemical name; NTP = National Toxicology Prograix: S103443 H1ITV3H 2 TONIHdOHOTHOV.INId €€ PENTACHLOROPHENOL 34 2. HEALTH EFFECTS There is evidence of mild-to-moderate renal toxicity in experimental animals as a result of subchronic/chronic oral administration of pentachlorophenol. The most frequently reported toxic effects seen in kidneys of rodents include increased organ weight and altered enzyme levels. Histopathologic effects are rarely seen. The possibility that impurities in pentachlorophenol may be responsible for the adverse effects observed is likely. Furthermore, some of the data discussed below have many inconsistencies. Purified pentachlorophenol (99% pure) induced and increase in kidney weight in rats fed this compound at similar doses for periods of 3-8 months (Johnson et al. 1973; Kimbrough and Linder 1978). In the Kimbrough and Linder (1978) study, this finding was believed to be compound related but not dose related, it only occurred in males, and it was not seen in animals treated with technical grade pentachlorophenol. It was demonstrated in the Johnson et al. (1973) study that kidney weight changes were evident at lower doses of technical pentachlorophenol than purified pentachlorophenol. In neither study were renal histopathological changes observed to accompany organ weight changes. Thus, the biological significance of these observations with regard to long- term toxicity is not known. Kidney weight and urine specific gravity were increased, and a dose-related incidence of kidney discoloration was observed in rats fed 1-30 mg/kg/day of Dowicide EC-7 for 24 months (Schwetz et al. 1978). Whether or not pigmentation constitutes an adverse effect is not known. Biochemical changes indicative of renal toxicity have also been reported in pentachlorophenol- treated animals. For example, after 15 days of oral exposure to purified pentachlorophenol at 10 or 15 mg/kg/day, young pigs exhibited statistically significant increased levels of blood urea nitrogen, but this effect was no longer significant after 30 days of treatment (Greichus et al. 1979). Proximal tubular alkaline phosphatase activity was decreased after 1 month of twice weekly gavage doses of 90% pure pentachlorophenol (40-160 mg/kg/day) administered to rats, but this effect was no longer evident after 3 months of treatment (Nishimura et al. 1980). The biological significance of these apparently transient renal effects with regard to long-term toxicity Is not known. Dermal/Ocular Effects. No studies were located regarding dermal/ocular effects in humans or animals after oral exposure to pentachlorophenol. PENTACHLOROPHENOL 35 2. HEALTH EFFECTS Other Systemic Effects. Significant (>10%) decreases in body weight gain were observed in several studies where both technical and pure pentachlorophenol were administered for intermediate or chronic durations to rats (Kimbrough and Linder 1978; Nishimura et al. 1980; Welsh et al. 1987). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans following oral exposure to pentachlorophenol. Evidence for pentachlorophenol-induced alterations in immune function was obtained from studies conducted in experimental animals. The available data indicate that, at doses of 0.5-100 mg/kg/day, pentachlorophenol affects a wide range of immune functions, such as humoral and cellular immunity, susceptibility to tumor induction, and complement activity. The majority of immunotoxic effects of pentachlorophenol appear to be related to the level of impurities in the technical product (e.g., polychlorinated dibenzo-p-dioxins and dibenzofurans). Studies that compared effects of technical grade to pure pentachlorophenol are reviewed below in an attempt to illustrate immunotoxic effects attributable to pentachlorophenol. Female B6C3F| mice exposed daily to 10-100 mg/kg of technical pentachlorophenol by gavage for 2 weeks exhibited a dose-related suppression of in vivo antibody response (IgM plaque-forming cells [PFC]) to sheep red blood cells (SRBC) when mice were immunized during exposure (Holsapple et al. 1987). This response was not seen following purified pentachlorophenol exposure. It was further observed that spleen cells from mice treated with technical grade penta- chlorophenol could still produce antibodies following in vitro immunization, indicating that the suppression seen following in vivo immunization was not due to a direct effect on antibody forming cells. Effects of dietary administration of both technical grade and purified pentachlorophenol for 10-12 weeks on the ability of male B6C3F; mice to resist syngeneic tumor growth, an indication of an organism’s state of immunosurveillance, were studied (Kerkvliet et al. 1982). Technical grade preparation induced a significant dose-independent enhancement of susceptibility to methylcholanthrene-induced sarcoma 1412 tumor growth, whereas the purified preparation had no PENTACHLOROPHENOL 36 2. HEALTH EFFECTS effect on this parameter. In another test of immunocompetence, treated mice were studied for their ability to resist secondary tumor growth induced by Maloney sarcoma virus (MSV). After exposure to technical grade pentachlorophenol, animals were inoculated with MSV which resulted in transient subcutaneous injection site tumors. Upon subsequent challenge with MSV- transformed tumor cells, a significant increase in mortality and secondary tumor susceptibility was seen in technical grade-treated animals but not in animals administered purified pentachloro- phenol. This result suggests a detrimental effect on both primary and secondary T-cell-dependent cytotoxic immune response. An increase in secondary splenic tumors was seen in animals treated with both grades of pentachlorophenol at a dose of 25 mg/kg/day. This was interpreted as a more sensitive indicator of immunocompetence suppression by purified pentachlorophenol. In a third test designed to evaluate macrophage competence, resistance to encephalomyocarditis virus (EMCV) was also studied in mice treated with both grades of pentachlorophenol. No effect was seen on susceptibility of either group of animals to EMCV-induced mortality. The investigators concluded that immunomodulatory effects observed with pentachlorophenol were due primarily, but not exclusively, to contaminants present in technical preparation. To further investigate the role of these impurities in immunotoxicity induced by technical penta- chlorophenol, the antibody (IgM) response to an SRBC challenge in C57BL/6 mice given single oral doses of both grades of pentachlorophenol was studied (Kerkvliet et al. 1985a). In agreement with results seen by Holsapple et al. (1987), technical grade pentachlorophenol induced a dose-related suppression of this response at a dose of 30 mg/kg/day whereas purified pentachlorophenol did not. Co-administration of HpCDD, one of the most prevalent chlorinated dibenzo-p-dioxin impurities in technical pentachlorophenol, with pure pentachlorophenol resulted in an immunosuppressive response that was similar in magnitude to that seen with technical grade pentachlorophenol or HpCDD alone. These results provide good evidence that impurities (particularly HpCDD) are responsible for immunotoxic effects attributed to technical grade penta- chlorophenol. Results from the next series of experiments conducted by these investigators further supported this hypothesis. Technical grade pentachlorophenol was fed to both C57BL/6 mice and DBA/2 mice for 6 weeks (Kerkvliet et al. 1985a). The former strain has a high-affinity aryl hydrocarbon (Ah) receptor and the latter a low-affinity Ah receptor. The ability of chlorinated dibenzo-p-dioxin and dibenzofuran congeners (that are present as impurities in pentachlorophenol) to bind to this receptor correlates with their toxicity and their ability to induce P-450 monooxygenase activity. Antibody response to SRBC was suppressed by 28% PENTACHLOROPHENOL 37 2. HEALTH EFFECTS (p<0.01) and 72% (p<0.01) in the two groups of C57BL/6 mice with different levels of technical grade pentachlorophenol, as opposed to 0% and 45% (p>0.01) in corresponding groups of D2 mice. Based on these results, the authors concluded that the immunosuppressive effect of technical grade pentachlorophenol was probably mediated by contaminant chlorinated dibenzo-p- dioxins and dibenzofurans via interaction with the Ah receptor. In a study designed to evaluate effects of dietary exposure to technical grade pentachlorophenol on T-cell, macrophage, and natural killer cell activity, C57BL/6 mice were administered technical grade pentachlorophenol for 8 weeks prior to conducting a number of in vitro immunofunction tests (Kerkvliet et al. 1985b). They found that T-cell and macrophage-mediated (cell-mediated) immunocompetence is relatively resistant to perturbation by technical grade pentachlorophenol. The only statistically significant change seen was a reduction in lymphoproliferative response in mixed lymphocyte culture. This finding contrasts with marked effects that technical grade penta- chlorophenol has on antibody-mediated immunity. The complement component of the immune system has also been found to be affected by exposure to technical grade pentachlorophenol, but not Dowicide EC-7, a preparation of 90% pentachlorophenol that contains reduced levels of chlorinated dibenzo-p-dioxins and dibenzofurans (see Table 2-2) (White and Anderson 1985). In this study, technical grade pentachlorophenol inhibited functional activity of all aspects of complement in a dose-dependent manner. This suppression was still seen up to 30 days after termination of treatment. No clinical signs of toxicity (e.g., increased incidence of infection) or other functional immunological deficiencies were reported to be associated with immunological effects discussed in this section. Therefore, these observed effects are of unknown biological significance. The highest NOAEL values and all LOAEL values from each reliable study for immunological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.4 Neurological Effects One report describing effects of ingestion of pentachlorophenol in humans was found in the literature (Haley 1977). In this case, an adult male intentionally ingested an estimated 4-8 ounces PENTACHLOROPHENOL 38 2. HEALTH EFFECTS of weed killer that contained 12% pentachlorophenol, 1.5% other chlorinated phenols, 82% aromatic petroleums, and 4.5% inert ingredients. Clinical signs observed upon subsequent hospital admission included pyrexia, diaphoresis, hyperkinesis, muscle twitching, tremors, epigastric tenderness, leg pain, tachypnea, and tachycardia. These neurologic symptoms are most likely the result of pentachlorophenol’s ability to uncouple oxidative phosphorylation, and not a direct toxic effect on central or peripheral nervous systems. The patient recovered through use of forced diuresis. Though this case report provides evidence for pentachlorophenol-induced neurotoxicity in humans, it is limited in that there was also concurrent exposure to other potentially neurotoxic compounds. The report also illustrates acute human toxicity of pentachlorophenol when mixed with nonaqueous materials. Results from animal studies demonstrate that the central nervous system is adversely affected by pentachlorophenol, most likely as a result of hyperthermia induced by uncoupling of oxidative phosphorylation. At the neurochemical level, transient changes in activity of some brain enzymes and decreased glial glutathione level were seen in rats administered technical grade pentachloro- phenol in drinking water for 14 weeks (Savolainen and Pekari 1979). These findings suggest another biochemical component to technical grade pentachlorophenol neurotoxicity. The possibility and extent of the role of technical grade contaminants in producing these effects are not known, although the study authors concluded that the neurochemical changes were most likely associated with the body burden of chlorophenols. Male Wistar rats (number per group unspecified) were administered pentachlorophenol (purity unspecified) in drinking water ad libitum. Group 1 received 0.3 millimoles (mM) for 60 days, Group 2 received 1.0 mM for 60 days, Group 3 received 1.0 mM for 90 days, and Group 4 received 3.0 mM for 120 days. A fifth group served as control (exact treatment unspecified). The sciatic nerves of all rats were examined by optical and electron microscopy. Animals in Groups 1 and 2 did not exhibit any changes as compared to controls. The animals in Groups 3 and 4 exhibited morphological changes in the myelin sheaths of the sciatic nerves. These included degenerative changes in 10% of the Types A and B fibers consisting of breaks in the myelin sheath and a variable loss of neurotubules, neurofilaments, and other axoplamic components. Type C fibers were unaffected. These changes were more marked in the Group 4 animals. While these results suggest that pentachlorophenol can cause neurotoxic changes in the morphology of peripheral nerves, since the purity of the pentachlorophenol tested was not PENTACHLOROPHENOL 39 2. HEALTH EFFECTS specified, it is not possible to determine whether these changes were due to pentachlorophenol itself or impurities present in technical pentachlorophenol. Other limitations associated with this study include a lack of protocol details (e.g., number of animals per group) and a lack of quantitative incidence data (Villena et al. 1992). The LOAEL for neurological effects in rats following intermediate exposure is recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.5 Reproductive Effects No studies were located regarding reproductive effects in humans after oral exposure to penta- chlorophenol. No standard reproduction studies in experimental animals were located in the literature. Available data suggest that, at adequate doses in pregnant rats, pentachlorophenol decreases survival of pups. Rats administered either 3 or 30 mg/kg/day pure pentachlorophenol in their diet for 62 days were mated and maintained on their respective diets during mating, gestation, and lactation (Schwetz et al. 1978). At the 30-mg/kg/day dose level, a reduction in mean body weight was observed in adult rats. Also, a significantly increased number of litters showed variations in development of skeletal structures. Except for significant (p<0.05) decreases in average litter size, neonatal survival, and mean neonatal body weights, no other measures of reproductive capacity were affected, and no adverse effects on maternal and fetal parameters were observed at the 3-mg/kg/day dose level. In an earlier study, Schwetz et al. (1974) observed a high incidence of resorptions in pregnant rats receiving 15 mg technical grade pentachlorophenol/kg/day or 30 mg purified pentachlorophenol/ kg/day during days 6-15 of gestation, but not in rats receiving 5 mg/kg/day. These NOAELSs and LOAELs are recorded in Table 2-1 and plotted in Figure 2-1. Although decreased litter size was reported in rats receiving 25 mg/kg both prenatally and postnatally, this effect was not statistically significant (Exon and Koller 1982). Embryolethality was also reported in rats fed purified pentachlorophenol at daily doses of 43 mg/kg for 181 days (Welsh et al. 1987). PENTACHLOROPHENOL 40 2. HEALTH EFFECTS 2.2.2.6 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to penta- chlorophenol. Many preparations of pentachlorophenol are contaminated with highly toxic substances, such as chlorinated dibenzo-p-dioxins. Therefore, the purity of pentachlorophenol tested must be considered when evaluating results. Six studies were located in the literature that provided data on teratogenic and fetotoxic effects of pentachlorophenol: four gavage studies (Courtney et al. 1976; Larsen 1976; Larsen et al. 1975; Schwetz et al. 1974) and two dietary studies (Exon and Koller 1982; Welsh et al. 1987). The results of these studies indicate that pentachlorophenol is not teratogenic in experimental animals. However, it is embryo- and fetotoxic and also produces maternal toxicity. Decreased average fetal weight was the only statistically significant (p<0.05) effect observed among end points evaluated when pregnant rats were administered 75 mg/kg/day pentachloro- phenol by gavage (purity unknown) on days 7-18 of gestation (Courtney et al. 1976). Micro- scopic and gross evaluation of fetal tissues was not reported. Developmental effects of purified (98% purity; with low nonphenolics) and technical grade penta- chlorophenol (88.4% purity; higher nonphenolic content) (see Table 2-2) in rats were investigated by administering pentachlorophenol at dose levels up to 50 mg/kg/day on days 8-11, 12-15, or 6-15 of gestation (Schwetz et al. 1974). Pentachlorophenol (both grades) was highly embryo- lethal and embryotoxic. Purified pentachlorophenol was slightly more toxic than technical grade in the maternal and fetal parameters measured. Maternal body weights in both groups were significantly (p<0.05) depressed. The NOAEL for technical grade pentachlorophenol (88% pure) was 5.8 mg/kg/day administered during days 6-15 of gestation. Slight changes in skeletal formation, such as lumbar spurs or supernumerary ribs, occured at doses of 15 mg/kg/day and above for both grades. Purified pentachlorophenol, however, produced a statistically significant increase in the incidence of delayed ossification of skull bones at levels as low as 5 mg/kg/day. This effect was used as the basis for the acute oral MRL. The apparent lack of a dose response at 50 mg technical grade pentachlorophenol/kg/day and 30 mg purified pentachlorophenol/kg/day relative to other dose levels was due to the high incidence of resorption that occurred at these PENTACHLOROPHENOL 41 2. HEALTH EFFECTS doses. Therefore, this study did not establish a NOAEL for fetotoxicity for purified pentachloro- phenol. The developing embryo was more susceptible to deleterious effects of pentachlorophenol given during early organogenesis (days 6-15 or 8-11) than during the late organogenesis period (days 12-15). In a later study (which was not a standard teratogenicity study), fetotoxic rather than teratogenic effects of pentachlorophenol were reported in pups from male and female rats that were mated after receiving 30 mg/kg/day of Dowicide EC-7 in the diet for 62 days (Schwetz et al. 1978). Treatment was continued during mating, gestation, and lactation. A significant decrease (p<0.05) in maternal body weight gain occurred on day 21 postpartum. No adverse effects were reported for fetuses or dams at a dietary level of 3 mg/kg/day. Malformations were observed in rat fetuses following administration of single doses of 60 mg/kg pentachlorophenol (purity not stated) to pregnant rats on days 8, 9, 10, 11, 12, or 13 of gestation (Larsen 1976; Larsen et al. 1975). Three of the four observed malformations (exencephaly, microphthalmia, and absent tail) occurred in litters exposed on day 9 of gestation (5.8% incidence). The fourth, dwarfism, occurred in a rat exposed on day 8. Treatment on day 9 or day 10 of gestation resulted in a significant (p<0.05) reduction in fetal weight gain (20% and 13%, respectively), with the greatest reduction occurring following treatment on day 9. Only negligible amounts of pentachlorophenol crossed the placenta following administration of a single oral dose of 60 mg/kg radiolabeled pentachlorophenol to rats on day 15 of gestation. The study authors therefore concluded that the minimal number of malformations produced may have resulted from toxic effects on the dams (a dose of 60 mg/kg is about 75% of the LDs) (Larsen et al. 1975). Effects of transplacental exposure of rats to chlorinated phenols have also been reported (Exon and Koller 1982). This study was designed to produce progeny that were exposed to technical grade pentachlorophenol (reported by the manufacturer to be 95% pure but upon analysis was determined to be 85.5% pure) levels in feed equivalent to 25 mg/kg both prenatally and postnatally. Although pentachlorophenol decreased litter size at the highest dose tested, this effect was not statistically significant. In an intermediate-duration dietary study, male and female rats were fed purified pentachloro- phenol (>99% pure) at daily doses of up to 43 mg pentachlorophenol/kg for 181 days (Welsh et al. 1987). Pentachlorophenol was embryolethal and maternally toxic at the highest dose tested. PENTACHLOROPHENOL 42 2. HEALTH EFFECTS Treated dams from this group gained less weight throughout pregnancy than did controls, but no maternal mortality was reported. Male fetuses from the 13-mg/kg/day dose group also exhibited decreased body weights, but no embryolethality was seen. This effect was statistically significant (p<0.05). The highest NOAEL values and all LOAEL values from each reliable study for developmental toxicity in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans or animals following oral exposure to pentachlorophenol. Genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer in humans following oral exposure to pentachloro- phenol. Carcinogenicity of orally administered pentachlorophenol has been tested in at least three studies using rats and mice (BRL 1968; Innes et al. 1969; NTP 1989; Schwetz et al. 1978). The purity of pentachlorophenol in these studies varied; this is an important factor to consider because penta- chlorophenol, during its production, is usually contaminated with chlorinated dibenzo-p-dioxins, some of which are animal carcinogens. NTP (1989) tested both technical grade pentachloro- phenol (TG-Penta), a 90% pure composite mixture of three technical grades of pentachloro- phenol, and Dowicide EC-7, a mixture containing 90% pure pentachlorophenol and fewer chlorinated dibenzo-p-dioxin impurities than TG-Penta (see Table 2-2). BRL (1968) tested Dowicide EC-7 as well. Schwetz et al. (1978) tested Dowicide EC-7. BRL administered Dowicide EC-7 (0 or 17 mg/kg/day) in the diet of weanling B6C3F| mice for 78 weeks (BRL 1968), while NTP (1989) administered Dowicide EC-7 (0, 18, 37, or 118 mg/kg/ day) in the diet of B6C3F, mice for 103 weeks. No significant elevation in incidence of cancer PENTACHLOROPHENOL 43 2. HEALTH EFFECTS occurred in the BRL study; however, in the NTP study, significant increases in incidence of tumors were observed. Male mice displayed significant dose-related increases in the incidence of adrenal medulla pheochromocytomas (benign and malignant) and hepatocellular adenomas and carcinomas. Female mice in the high-dose group displayed significant increases in incidences of hepatocellular adenoma and carcinoma, in pheochromocytomas (benign and malignant), and in hemangiosarcomas (spleen and liver). The differences between the two studies were that BRL tested for a shorter period of time, used fewer animals per group, had higher mortality in the dose group leaving fewer animals to be at risk of developing tumors, and used only one dose that was one-sixth of the highest dose used in the NTP study, and therefore, was probably not the maximum tolerated dose. NTP (1989) also tested TG-Penta, a composite mixture of three technical grades of pentachloro- phenol. This mixture contained a higher percentage of chlorinated dibenzo-p-dioxin contaminants than did the Dowicide EC-7 mixture (see Table 2-2). Groups of male and female BoC3F,; mice were given diets that contained 0, 100, or 200 ppm TG-Penta (equivalent to 0, 18, or 35 mg/kg/ day, respectively) or Dowicide EC-7 (as described above for 103 weeks). Survival was reduced in all groups, including controls, when compared to historical controls. Male mice displayed a significant increase over the male control incidence in tumors of the adrenal medulla (benign and malignant pheochromocytomas combined) and liver (adenomas and carcinomas combined). Treated female mice displayed a significant increase over female controls with regard to incidence of hemangiosarcomas of the spleen and liver. A high level of chlorinated dibenzo-p-dioxins was found in the TG-Penta mixture. Chlorinated dibenzo-p-dioxin exposure has been associated with an increased incidence of liver tumors in treated mice but not with pheochromocytomas or hemangiosarcomas (NCI/NTP 1980). Although this study is limited because of unusually low survival in the male TG-Penta control group, the occurrence of rare hemangiosarcomas was considered a carcinogenic response due to pentachlorophenol exposure. In an earlier study, Dowicide EC-7 was administered to rats at dietary levels of 0, 1, 3, 10, or 30 mg/kg/day in males and females for 22 months and 24 months, respectively (Schwetz et al. 1978). No significant increases in incidence of tumors were observed during this study. The study was limited however because a small number of animals was tested, no data on survival were provided to evaluate if enough animals survived for a long enough period of time to develop tumors, and it is not known if the maximum tolerated dose was attained. PENTACHLOROPHENOL 44 2. HEALTH EFFECTS The most convincing evidence that 90% pure pentachlorophenol is carcinogenic to mice following ingestion comes from the NTP (1989) bioassay. This study was generally well conducted, taking into account the lifetime of the study animal, that gross necropsy and histopathology were completed on all suitable animals, and that percentages of the maximum tolerated dose were administered to determine carcinogenic response. It is limited because of the unusually low survival of the male TG-Penta control group. EPA has classified pentachlorophenol as a Group B2 substance (probable human carcinogen) (IRIS 1992). A cancer potency factor of 0.12 (mg/kg/day)! has been calculated based on the NTP (1989) data. This cancer potency factor translates to estimated upper-bound unit risk levels of 9x1073, 9x104, 9x10, 9x10, and 9x10” mg/kg/day for cancer risks of 1 in 1,000, 1 in 10,000, 1 in 100,000, 1 in 1,000,000, and 1 in 10,000,000, respectively (see Figure 2-1). The CELs for pentachlorophenol are recorded in Table 2-1 and plotted in Figure 2-1, and the estimated upper-bound human cancer risk levels are plotted in Figure 2-1. 2.2.3 Dermal Exposure No studies considered suitable for presentation in a table describing significant levels of dermal exposure to pentachlorophenol were found. 2.2.3.1 Death In most instances, death in humans exposed to pentachlorophenol was a result of occupational exposure or use of pentachlorophenol-containing products in the home by individuals who did not employ proper precautionary measures. Though the primary route of exposure in all of these studies was believed to be dermal, the probability that inhalation exposure also occurred must be considered. All of these reports are limited in that the possibility of concurrent exposure to other potentially toxic substances in technical grade pentachlorophenol as well as concurrent exposure to other toxic substances (e.g. lindane, dieldrin) cannot be excluded, and because the penta- chlorophenol exposure level and duration cannot be quantified because appropriate measurements were not taken at the time. It should be noted that occupational exposure to pentachlorophenol has been strictly limited not only by use patterns but by application PENTACHLOROPHENOL 45 2. HEALTH EFFECTS procedures, and all household uses of pentachlorophenol have been banned. Therefore, exposure to pentachlorophenol resulting in death as described in this section is currently improbable with the exception of hazardous waste workers involved in the clean up of pentachlorophenol- containing ponds. It should also be noted that the deaths discussed below resulted from the use of a formulation that had a different composition (e.g., presence of more impurities) than the pentachlorophenol that is currently used. Dermal exposure was also possible and that other compounds in the herbicide could have contributed to death. Five cases of fatal blood dyscrasias were reported. Reports followed pentachlorophenol exposures after 1-month to 4-year intervals—three as a result of industrial exposure and two from home use (Roberts 1963, 1981, 1990). Cause of death in all cases was reported to be either aplastic anemia or red blood cell aplasia (see Section 2.2.3.2, Hematological Effects). In another case, a 33-year- old man died following 3 weeks of daily exposure to pentachlorophenol dust in a chemical plant (Gray et al. 1985). Clinical signs, chemistries, and postmortem findings revealed functional and degenerative changes in most organ systems. Deaths attributed to pentachlorophenol were also reported in a male working as a wood preserver for 1 week (Bergner et al. 1965), five herbicide sprayers exposed once (Gordon 1956), and nine sawmill workers exposed for 3-30 days (Menon 1958). Deaths reported by Gray et al. (1985), Bergner et al. (1965), and Menon (1958) were all due to hyperthermia that resulted from uncoupling of oxidative phosphorylation by pentachloro- phenol. Manifestations of overexposure were chiefly those associated with hyperthermia: flushing, intense thirst, sweating, weakness, and occasionally, muscle spasms. Toxic effects seen in these fatalities will be discussed in sections dealing with specific organ toxicity. Hyperthermia is the major factor leading to death following fatal pentachlorophenol exposure in humans. One report of death following dermal exposure in experimental animals was found in the reviewed literature (Deichmann et al. 1942). Eight out of 20 rabbits administered dermal applications of 4% pentachlorophenol in fuel oil for 6-61 weeks died of unspecified causes. The vehicle contained known toxic substances (e.g., polyaromatic hydrocarbons), which may have contributed to the lethal effects observed. PENTACHLOROPHENOL 46 2. HEALTH EFFECTS 2.2.3.2 Systemic Effects Most of the literature reviewed concerning systemic effects of dermal exposure to pentachloro- phenol in humans described case reports of individuals exposed either occupationally or in the home during misuse of pentachlorophenol-containing solutions as a result of failure to adhere to appropriate precautionary measures. The predominant route of exposure in such cases is dermal, but the possibility of some inhalation exposure cannot be ruled out. All of these reports are limited because the possibility of concurrent exposure to other potentially toxic substances in technical grades of pentachlorophenol cannot be excluded, and because the pentachlorophenol exposure level and duration were not quantified. The organs or systems most often affected in these situations are the liver, kidneys, skin, blood, lungs, and perhaps the gastrointestinal tract. The effects observed are most likely secondary to hyperthermia generated by uncoupling of oxidative phosphorylation (see Section 2.4). No studies were located regarding cardiovascular or musculoskeletal effects in humans or animals after dermal exposure to pentachlorophenol. The only information found on pentachlorophenol- induced adverse effects in experimental animals described local dermatological effects (such as mild-to-severe irritation and necrosis, depending on concentration and duration of contact). Respiratory Effects. A 33-year-old chemical worker died following exposure to pentachloro- phenol for 3 weeks (Gray et al. 1985). He exhibited tachypnea (respiratory rate, 56 breaths/ minute). Autopsy findings included lungs that were heavy, congested, and edematous. Microscopic examination of lungs revealed congestion, edema, and widespread intraalveolar hemorrhage. These may have been secondary to general pentachlorophenol-induced mitochondrial derangement, leading to hyperthermia (rectal temperature, 105°F). Gastrointestinal Effects. Except for anecdotal reports of abdominal pain, nausea, and vomiting in humans occupationally exposed to pentachlorophenol (Gordon 1956; Menon 1958), no studies were located regarding gastrointestinal effects in humans or animals following dermal exposure to pentachlorophenol. Hematological Effects. Incidents of fatal hematological disorders were found in case reports following pentachlorophenol exposure (level and duration not specified) as a result of PENTACHLOROPHENOL 47 2. HEALTH EFFECTS predominantly dermal exposure. Thirteen cases of aplastic anemia, pure red blood cell aplasia, or severe pancytopenia with abnormal marrow have been reported, eight of which resulted in death (Roberts 1981, 1990). A case of intravascular hemolysis was attributed to pentachlorophenol following both dermal and inhalation exposure (Hassan et al. 1985). Hepatic Effects. Most of the studies reviewed concerning hepatic effects of dermal exposure to pentachlorophenol in humans described case reports of individuals exposed either occupationally or in the home following the use of pentachlorophenol-containing solutions by individuals who did not employ appropriate precautionary measures. As was pointed out in the discussion of hepatic effects associated with oral ingestion of pentachlorophenol (Section 2.2.2.2), there is strong evidence in experimental animals that toxic effects of technical grade pentachlorophenol may be predominantly due to certain impurities. Information regarding pentachlorophenol-induced hepatic toxicity in humans following dermal exposure discussed below is subject to some doubt regarding the extent to which adverse effects seen can be attributed to pure pentachlorophenol. Hepatic enlargement has been observed in herbicide sprayers (Gordon 1956), in neonates exposed for a short time via contaminated diapers and bed linen in a hospital nursery (Armstrong et al. 1969; Robson et al. 1969), and in a chemical worker exposed to pentachlorophenol dust for 3 weeks (Gray et al. 1985). Autopsy findings in those affected individuals who died revealed fatty infiltration of the liver (in the neonates) and severe centrilobular congestion with hepatocellular fat accumulation (in the chemical worker). Centrilobular degeneration was also observed in a liver specimen from a worker who dipped wood in a preservative that contained 4.1% penta- chlorophenol every day for 1 week (Bergner et al. 1965). Evidence of liver damage was seen in an epidemiologic study of adult males occupationally exposed to pentachlorophenol in wood- treatment plants or as farmers or pest control operators in Hawaii (Klemmer 1972). This evidence consisted of elevated SGOT and SGPT levels following chronic, predominantly dermal exposure to pentachlorophenol. Hyperthermia induced by pentachlorophenol may be a major factor leading to liver injury. Renal Effects. Three reports were found that described renal toxic effects following dermal exposure to pentachlorophenol in humans. All involved either occupational exposure or accidental poisoning with the predominant route of exposure being dermal, but the possibility of inhalation exposure cannot be excluded. In one instance, a 3-year-old girl was exposed to penta- chlorophenol via a pesticide-contaminated domestic water supply. Transient disruption of acid- PENTACHLOROPHENOL 48 2. HEALTH EFFECTS base equilibrium and metabolic balance as evidenced by acidosis, aminoaciduria, and ketonuria suggested the occurrence of renal dysfunction in this child (Chapman and Robson 1965). An autopsy conducted on a worker who dipped wood in a preservative that contained 4.1% penta- chlorophenol every day for 1 week revealed mild renal tubular degeneration (Bergner et al. 1965). Finally, evidence for pentachlorophenol-induced impaired glomerular filtration and tubular function was reported in 18 workers employed at a wood-treatment facility (Begley et al. 1977). These findings consisted of depressed creatinine clearance and phosphorus reabsorption. Considerable improvement in these symptoms was seen following a 20-day absence from work. These data suggest that the renal toxicant effects of technical grade pentachlorophenol are reversible. The extent to which contaminants of technical grade pentachlorophenol are responsible for the effects discussed above is not known. Hyperthermia may also be a mechanism of renal injury in individuals that are acutely overexposed to pentachlorophenol. Dermal/Ocular Effects. Reports of dermatitis and corneal damage resulting in permanent impairment of vision associated with repeated dermal exposure to sodium pentachlorophenate were found in the reviewed literature (EPA 1987¢). West German workers employed in a plant that produced pentachlorophenol complained of severe skin eruptions (Baader and Bauer 1951). Transient localized redness and pain subsequent to immersion of the hands in a 0.4% penta- chlorophenol solution for 10 minutes were exhibited by an adult male (Bevenue et al. 1967). Two cases of pemphigus vulgaris and one of chronic urticaria (both examples of severe skin lesions) attributed to nonoccupational chronic pentachlorophenol exposure (i.e., via contact with wood treated with pentachlorophenol) have been described (Lambert et al. 1986). The presence of skin abnormalities (type not specified) was reported in some residents of log homes treated with pentachlorophenol (Hosenfeld et al. 1986). The dermal effects discussed above may have resulted from impurities present in the pentachlorophenol resulting from the manufacturing process. Chloracne (incidence determined by company medical records) was also reported in 47 of 648 (7%) pentachlorophenol production workers exposed for an average of 1.4 years (O'Malley et al. 1990). Limitations associated with this study are related to using medical records as the primary source of data and include (1) missing or inconsistent diagnoses, (2) changes in clinical definition of the disease over the course of study, (3) discrepancy between documentation of onset of disease as compared to date of diagnosis, and (4) missing records. While many of these limitations were addressed by the investigators, the use of medical records as the primary source PENTACHLOROPHENOL 49 2. HEALTH EFFECTS of data still limits the conclusions that can be drawn from this study. There was no relationship between length of employment in the pentachlorophenol department and risk of chloracne. In addition, workers that had documented evidence of direct skin contact with pentachlorophenol had a fourfold increase in incidence of chloracne when compared to workers with no documented evidence of direct skin contact. The pentachlorophenol produced in this plant was contaminated with HxCDD, HpCDD, OCDD, and dibenzofurans (all substances known to cause chloracne). Therefore, the effects seen in this study may be due to contaminants of pentachlorophenol rather than pure pentachlorophenol. The hypothesis that chloracne observed in these workers is due to contaminants present in technical grade pentachlorophenol is supported by observations in animals. Technical grade pentachlorophenol applied to rabbit ears produced acne, whereas pure pentachlorophenol did not (no further details provided) (Johnson et al. 1973). Pentachlorophenol-induced toxic effects on the skin of experimental animals have also been reported. A single application of pentachlorophenol (1,111 mg/kg in 95% ethyl alcohol or 150 mg/kg in pale paraffin oil) resulted in gross changes such as pronounced edema and inflammation leading to wrinkling, cracking, desquamation, and hair loss. Microscopic changes observed include widespread foci of atrophy and necrosis, thinning and disappearance of upper skin layers, and hyperkeratinization and hypertrophy of hair follicles (Deichmann et al. 1942). Single dermal applications of 250 mg/kg of a 10% aqueous sodium pentachlorophenate solution to rabbits did not result in dermal irritation. Repeated application of lower doses of pentachloro- phenol (40 mg/kg in mineral oil) to rabbits for 21 days induced no irritation, whereas daily application of 10-50 mg/kg of a 4% solution of pentachlorophenol in fuel oil for 6-61 weeks resulted in pronounced dermal effects, and daily application of 63 mg/kg of an aqueous sodium pentachlorophenate solution for 32 days was without effect (Deichmann et al. 1942). The toxic effects of dermal exposure to pentachlorophenol appear to be most severe following high-dose, acute exposure to pentachlorophenol in fuel oil. Other Systemic Effects. A brief report provided evidence that prolonged exposure to commercial pentachlorophenol-containing wood preservatives may be associated with reproductive disorders that are secondary to endocrine dysfunction (for details, see Section 2.2.1.2, Other Systemic Effects) (Gerhard et al. 1991). PENTACHLOROPHENOL 50 2. HEALTH EFFECTS 2.2.3.3 Immunological Effects Two cases of pemphigus vulgaris and one of chronic urticaria (skin diseases with an immunologic etiology) have been attributed to nonoccupational exposure to pentachlorophenol (see Section 2.2.3.2, Dermal/Ocular Effects) (Lambert et al. 1986). A brief report provided evidence that prolonged exposure to commercial pentachlorophenol-containing wood preservatives may be associated with reproductive disorders that are secondary to immunologic dysfunction (for details, see Sections 2.2.1.3 and 2.2.1.5) (Gerhard et al. 1991). No studies were located regarding immunological effects in animals following dermal exposure to pentachlorophenol. 2.2.3.4 Neurological Effects The bulk of the studies reviewed concerning neurotoxic effects of dermal exposure to penta- chlorophenol are case reports of occupational or accidental exposure. Though the primary route of exposure in all of these studies was believed to be dermal, the possibility that inhalation exposure also occurred must be considered. In most instances, exposure level and/or duration were not quantified and concurrent exposure to other toxic substances was possible. Signs indicative of central nervous system toxicity (most likely the result of hyperthermia induced by uncoupling of oxidative phosphorylation) were observed in both nonfatal and fatal exposures to technical grade pentachlorophenol. Symptoms observed in a 3-year-old girl exposed to penta- chlorophenol via the domestic water supply included intermittent delirium, fever, and convulsions (Chapman and Robson 1965). Neonates exposed to pentachlorophenol in contaminated hospital bed linens for a short time exhibited excessive sweating, tachypnea, and respiratory distress (Robson et al. 1969). A 33-year-old chemical worker who died after short-term exposure to pentachlorophenol dust exhibited signs of central nervous system toxicity (lethargy and tachypnea) (Gray et al. 1985). Autopsy revealed cerebral edema with focal swelling of the myelin sheath. These histopathologi- cal changes may also be the result of pentachlorophenol-induced hyperthermia. PENTACHLOROPHENOL 51 2. HEALTH EFFECTS Maximal motor and sensory nerve conduction velocities of the ulnar and/or median nerve were studied in factory workers with a mean exposure duration to pentachlorophenol of 12 years (Triebig et al. 1987). These parameters were always within the normal range. The study authors concluded that chronic occupational exposure to pentachlorophenol does not adversely affect the peripheral nervous system. No studies were located regarding neurological effects in animals following dermal exposure to pentachlorophenol. 2.2.3.5 Reproductive Effects A brief report provided evidence that prolonged exposure to commercial pentachlorophenol- containing wood preservatives may be associated with reproductive disorders that are secondary to endocrine and/or immunologic dysfunction (for details, see Section 2.2.1.2, Other Systemic Effects; see also Sections 2.2.1.3 and 2.2.1.5) (Gerhard et al. 1991). No studies were located regarding reproductive effects in animals following dermal exposure to pentachlorophenol. 2.2.3.6 Developmental Effects No studies were located regarding developmental effects in humans or animals following dermal exposure to pentachlorophenol. 2.2.3.7 Genotoxic Effects Since occupational exposure to pentachlorophenol may involve dermal as well as inhalation exposure, see Section 2.2.1.7 for a discussion of genotoxic effects in humans following dermal exposure to pentachlorophenol. No studies were located regarding genotoxic effects in animals following dermal exposure to pentachlorophenol. PENTACHLOROPHENOL 52 2. HEALTH EFFECTS Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer Epidemiological studies and case reports described in Section 2.2.1.8 (in which dermal exposure was also likely) are inadequate and cannot be used to evaluate the carcinogenic potential of pentachlorophenol in humans. Only one study was located in which investigators topically administered pentachlorophenol to animals (Boutwell and Bosch 1959). These investigators applied a 20% solution of commercial grade pentachlorophenol in benzene to shaved dorsal skin of mice twice a week for 13 weeks. Mice were previously treated with a dose of 0.3% dimethylbenzanthracene (DMBA) in benzene to induce skin cancer. No increase in DMBA-induced skin tumors resulted from pentachloro- phenol treatment. This study was designed to determine if pentachlorophenol was a tumor promoter and was therefore severely limited in its ability to detect a carcinogenic effect caused by pentachlorophenol because of administration of an insufficient dose over a short treatment period. However, based on results of this study, pentachlorophenol was inactive as a promotor of skin tumors in mice. 2.3 TOXICOKINETICS Pentachlorophenol is absorbed following inhalation, oral, and dermal exposure. Limited information is available regarding distribution of pentachlorophenol in humans. Analysis of tissues and fluids collected at autopsy from 21 people described as "normal" (level and duration of exposure to pentachlorophenol was not specified), for whom pentachlorophenol exposure was not the cause of death, revealed that the highest concentrations of pentachlorophenol were located in the liver, kidneys, and brain. Lower levels were also detected in the spleen and body fat (Grimm et al. 1981). The source, route, and duration of pentachlorophenol exposure in these individuals were not specified. Results from animal and human studies indicate that pentachlorophenol is not readily metabolized, as evidenced by a large portion of the administered dose being excreted in urine unchanged in all species studied. Extensive plasma protein binding of pentachlorophenol discussed in Section 2.3.2.2 may account for the low degree of metabolism because protein-bound material is not readily distributed to tissues. However, the available human and animal data PENTACHLOROPHENOL 53 2. HEALTH EFFECTS indicate that metabolism of pentachlorophenol does occur in the liver, and the major pathways are conjugation to form the glucuronide and oxidative dechlorination to form tetrachlorohydro- quinone (TCHQ). The primary route of pentachlorophenol elimination in all species studied, including humans, by all routes of exposure is urine. Approximately 74% and 12% (total of 86%) of pentachlorophenol ingested by humans was eliminated as pentachlorophenol and its glucuronide conjugate, respectively (Braun et al. 1979). In rodents, from 60% to 83% of the administered oral dose is eliminated in the urine (Ahlborg et al. 1974; Braun et al. 1977; Larsen et al. 1972; Reigner et al. 1991); in monkeys, 45-75% of the administered oral dose is eliminated in the urine (Braun and Sauerhoff 1976) (see Section 2.3.3 for a discussion of the metabolites of pentachlorophenol excreted in each species). Fecal elimination of pentachlorophenol and its metabolites accounted for 4% of the administered oral dose in humans, 4-34% of the administered oral dose in rodents, and 4-17% in monkeys. Only trace amounts were eliminated in expired air. The pharmacokinetic profile of pentachlorophenol excretion following single doses is species- and possibly sex-dependent. Elimination was rapid and biphasic in rats (Braun et al. 1977; Reigner et al. 1991) and slow and first-order in monkeys and humans following oral exposure (Braun and Sauerhoff 1976; Braun et al. 1979). Enterohepatic circulation and plasma protein binding influence the elimination kinetics of pentachlorophenol, but no data are available to assess whether the elimination kinetics of pentachlorophenol are dependent on its concentration in blood. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure Information regarding absorption of pentachlorophenol by humans following inhalation exposure comes primarily from occupational case reports. Evidence for absorption of pentachlorophenol by humans is provided by the observation that pentachlorophenol levels in urine and plasma of exposed workers are significantly elevated when compared with those of unexposed workers (Casarett et al. 1969; Jones et al. 1986; Pekari et al. 1991). Levels of pentachlorophenol detected in blood and urine of residents of log homes treated with pentachlorophenol correlated with ambient concentrations in the homes, indicating absorption of the chemical (Cline et al. 1989; Hosenfeld et al. 1986). The usefulness of these data is limited because the possibility of dermal exposure cannot be excluded. In an attempt to measure inhalation absorption of pentachloro- PENTACHLOROPHENOL 54 2. HEALTH EFFECTS phenol in humans, two volunteers were exposed to pentachlorophenol in an enclosed area for 45 minutes while they applied pentachlorophenol to wood with a brush (Casarett et al. 1969). Ambient pentachlorophenol concentrations were 0.230 and 0.432 ng/m>. The extent of penta- chlorophenol absorption in these two subjects was calculated to be 88% and 76% of the total potential inhaled dose, based on measurements of respiratory rates during exposure, total urinary pentachlorophenol recovered for up to 1 week postexposure, and tidal volume estimates. These data indicate that pentachlorophenol is readily absorbed through the lungs of humans. Limited data are available to assess the extent of pentachlorophenol absorption following inhalation exposure in animals. Pulmonary absorption of pentachlorophenol in rats has been demonstrated to occur readily; 70-75% of radioactivity from a single 20-minute inhalation exposure (at a concentration calculated by the authors to be equivalent to 5.7 mg ['*C]-penta- chlorophenol/kg) was recovered in urine, plasma, liver, and lung by 24 hours postexposure (Hoben et al. 1976¢). It can be concluded from the available human and animal data that inhalation of pentachlorophenol vapors by individuals living in close proximity to hazardous waste sites where substantial levels of pentachlorophenol are released into air would result in absorption of this chemical. 2.3.1.2 Oral Exposure Results of studies in humans (Braun et al. 1979; Uhl et al. 1986) and animals (Ahlborg et al. 1974; Braun and Sauerhoff 1976; Braun et al. 1977; Meerman et al. 1983; Reigner et al. 1991) indicate that pentachlorophenol and its sodium salt are readily absorbed following oral administration. Oral absorption of pentachlorophenol (as the sodium salt in water) in humans was determined to be first order, with peak blood levels of 0.248 pg/L pentachlorophenol being achieved within 4 hours of ingestion of 0.1 mg sodium pentachlorophenate/kg by four healthy male volunteers (Braun et al. 1979). The average half-life of absorption was calculated to be approximately 1.3 hours, indicating that oral absorption of pentachlorophenol in humans is rapid. Oral absorption of pentachlorophenol by rats and monkeys was compared following administration of single oral doses in corn oil of 10 mg [14C]-pentachlorophenol/kg (monkeys) (Braun and Sauerhoff 1976) and 10 or 100 mg [1*C]-pentachlorophenol/kg (rats) (Braun et al. 1977). In both species, absorption through the gastrointestinal tract was rapid; females in both species exhibited PENTACHLOROPHENOL 55 2. HEALTH EFFECTS faster absorption than males as evidenced by different rate constants of absorption. These rate constants were 1.95 hour” and 1.52 hour! for male and female rats, respectively, and 0.215 hour’! and 0.383 hour’! for male and female monkeys, respectively. The half-lives of absorption were 3.64 and 1.81 hours, for male and female monkeys, respectively. Peak blood levels of approximately 60 pg pentachlorophenol/g plasma were achieved in both sexes of rat within 4-6 hours, and peak plasma levels of 10-30 pg pentachlorophenol/g plasma were reached by 12-24 hours in both sexes of monkey. Absorption of pentachlorophenol through the gastrointestinal tract was extensive in both species following administration of a single dose of [4C]-pentachlorophenol as evidenced by more than 90% recovery of radioactivity in urine, feces, expired air, tissues, and carcass. Based on these results, Braun et al. (1979) concluded that the absorption profile of pentachlorophenol in humans was more like that seen in rats than in monkeys. A limitation associated with the Braun et al. (1977) study, however, is that instead of taking multiple blood samples from the same animal, two animals were killed at different times to obtain the kinetic profile. Use of pooled data such as these may have provided inaccurate data for modeling. Similar results were obtained in another study in rats using a lower dose (2.5 mg/kg) of pentachlorophenol (Reigner et al. 1991). Peak plasma concentrations (7.3%+2.8 pg/mL) were achieved between 1.5 and 2 hours after administration. Absorption appeared to be first order and fit a one-compartment model in three of five animals tested. Half-life of absorption varied between 0.25 and 1.50 hours. Based on the results of this study, the authors concluded that pentachlorophenol is virtually completely absorbed after oral administration in rats. These same investigators studied the pharmacokinetics of pentachlorophenol in B6C3F | mice following the administration of a single gavage dose of 15 mg/kg (Reigner et al. 1992b). Peak plasma concentrations (28+7 pg/mL) were achieved between 1.5 and 2 hours after administration. Half- life of elimination from the blood averaged 5.80.6 hours. Based on the results of this study, the study authors concluded that pentachlorophenol is virtually completely absorbed after oral administration in mice. The extent of absorption of pentachlorophenol or sodium pentachlorophenate from the gastrointestinal tract was studied in rats allowed free access to drinking water that contained a 1.4- millimolar (mM) solution of sodium pentachlorophenate (288 mg/L) or food that contained 350 ppm pentachlorophenol or sodium pentachlorophenate (Meerman et al. 1983). Based on PENTACHLOROPHENOL 56 2. HEALTH EFFECTS analysis of pentachlorophenol plasma concentrations over a 24-hour period and comparison with parameters obtained after intravenous administration, the study authors concluded that absorption of pentachlorophenol and sodium pentachlorophenate under these conditions was essentially complete. 2.3.1.3 Dermal Exposure Using human abdominal skin (dermis and epidermis) obtained at autopsy, it has been demonstrated that 62% of pentachlorophenol in diesel oil solution penetrated skin in vitro, while only 16% of an aqueous solution of sodium pentachlorophcnate penetrated skin (Horsman ct al. 1989). EPA estimated 50% absorption of pentachlorophenol in oil formulations and 10% absorption for aqueous formulations based on rat oral LDg, data (EPA 1984). Thus, it appears that pentachlorophenol is absorbed to a much greater extent in an oily solution than in an aqueous solution following dermal exposure in humans. The only other available information on dermal absorption of pentachlorophenol and its salts by humans comes from occupational case studies in which elevated levels of pentachlorophenol have been detected in urine and plasma of workers who handle pentachlorophenol-treated wood and/or do not wear adequate personal protective gear when working in areas where pentachlorophenol is being sprayed (Jones et al. 1986). In addition, numerous case reports describe occurrence of severe toxicity and/or death in individuals whose exposure to pentachlorophenol is presumed to be predominantly via the dermal route (Gray et al. 1985; Robson et al. 1969; Wood et al. 1983). In a study employing Rhesus monkeys, pentachlorophenol was well-absorbed following percutaneous application in soil or in acetone (Wester et al. 1993). Under the conditions of this study (0.7 pg/em? in soil and 0.8 pg/em? in acetone of 14¢-pentachlorophenol applied for 24 hours to abdominal skin), 24.4+6.4% of the applied dose in soil and 29.2+5.8% of the applied dose in acetone were absorbed. These results indicate that pentachlorophenol is readily absorbed following dermal exposure, and is bioavailable from soil. Furthermore, the half-life of *C excretion was 4.5 days for both dermal application vehicles as well as following intravenous injection. PENTACHLOROPHENOL 57 2. HEALTH EFFECTS 2.3.2 Distribution Because of the lack of human data, the results of animal studies only will be discussed in this section. 2.3.2.1 Inhalation Exposure Information regarding distribution of pentachlorophenol following inhalation exposure in animals is limited. Distribution of pentachlorophenol was evaluated following single and multiple (five) 20-minute inhalation exposures to concentrations calculated by the authors to be equivalent to a dose of 5.7 mg pentachlorophenol/kg body weight by measuring concentrations of pentachloro- phenol in liver, lungs, blood, and urine only (Hoben et al. 1976¢). Rapid distribution away from the site of exposure was apparent after a single exposure since only 1.8% of the administered dose was present in lungs immediately after exposure. By 24 hours postexposure, approximately 55% of the administered dose was recovered in urine, 7% in plasma, 9% in liver, and 0.7% in lung. These data indicate that pentachlorophenol was cleared rapidly, and only small amounts accumulated in the tissue samples studied. Repeated-exposure experiments support the observation that pentachlorophenol does not accumulate in rats following inhalation exposure. By 24 hours after the last (fifth) exposure, 70% of the administered dose was recovered in urine, 5% in plasma, 4% in liver, and 0.3% in lung. It is not clear from these data where pentachlorophenol was distributed immediately following exposure, but high levels in urine suggest that pentachloro- phenol was cleared rapidly and did not reach an appreciable body burden following repeated exposure. Binding of pentachlorophenol to plasma proteins influences its distribution (see Section 2.3.2.2). Binding of pentachlorophenol to plasma proteins varies linearly with increasing dose following inhalation exposure (Hoben et al. 1976d). No studies were located regarding distribution of pentachlorophenol in animals following long-term inhalation exposure. 2.3.2.2 Oral Exposure Distribution studies in rats conducted 9 days after oral administration of a single dose of 10 mg ['4C]-pentachlorophenol/kg body weight in corn oil demonstrated that the highest levels of radioactivity are found in liver and kidneys and lower levels are found in brain and fat tissue. Radioactivity was also detected in lungs, testes, ovaries, heart, and adrenal glands. Levels of PENTACHLOROPHENOL 58 2. HEALTH EFFECTS radioactivity were uniformly higher in plasma and tissues of females as compared to males, though the distribution pattern was qualitatively the same (Braun et al. 1977). A similar distribution pattern was observed by Larsen et al. (1972) in rats 40 hours after gavage administration of 37-41 mg ['4C]-pentachlorophenol/kg body weight in corn oil. Distribution of [*C]-pentachlorophenol was measured in two monkeys 360 hours after oral administration of a single dose of 10 mg [14C]-pentachlorophenol/kg body weight. Approximately 11% of administered radiolabel was found in the body at the time of analysis; 80% of this activity was in the liver and in the large and small intestines. These data suggest that the monkey differs from the rat with regard to distribution of orally absorbed pentachlorophenol. There appears to be extensive biliary secretion and enterohepatic circulation of pentachlorophenol in the monkey as evidenced by the long half-life of pentachlorophenol in the body of monkeys and the fact that most of the radiolabel still present in the body 360 hours after administration was in the liver and large and small intestines (Braun and Sauerhoff 1976). Binding of pentachlorophenol to plasma proteins plays a role in the distribution of pentachloro- phenol. Tissue/plasma ratios and renal clearance rates following oral administration of penta- chlorophenol were much lower than would be predicted, based on the octanol/water partition coefficient and glomerular filtration rate (Braun et al. 1977). This could be explained by extensive binding of pentachlorophenol to plasma proteins. The authors subsequently demonstrated using an in vitro diafiltration technique that 95% of pentachlorophenol in plasma is protein bound (Braun et al. 1977). In another experiment in rats, 97.1+2.0% of the administered dose of pentachlorophenol was found bound to plasma proteins as compared to plasma lipoproteins (GOmez-Catalan et al. 1991). Protein binding can result in lower levels being distributed to tissues (i.c., liver and kidney) for metabolism and excretion and increased retention in the body. However, even though plasma protein binding of pentachlorophenol may slow its excretion, it is more likely that binding actually lowers the toxicity of this chemical because bound toxicants cannot diffuse out of capillaries into surrounding tissue where they can cause injury. 2.3.2.3 Dermal Exposure No studies were located regarding distribution of pentachlorophenol in humans or animals after dermal exposure to pentachlorophenol. PENTACHLOROPHENOL 59 2. HEALTH EFFECTS 2.3.2.4 Other Routes of Exposure Distribution of radioactivity in mice following intraperitoneal and subcutaneous administration of single doses of [4C]-pentachlorophenol has been reported (Jakobson and Yllner 1971). Only 0.4-6% of the administered dose was found in tissues 96 hours after intraperitoneal injection of 14.8-37.2 mg [14C]-pentachlorophenol/kg body weight. The highest concentrations of radiolabel were found in the gall bladder, liver, stomach wall, and gastrointestinal contents, indicating the occurrence of biliary secretion of pentachlorophenol. Lesser amounts of radiolabel were found in the kidneys, heart, and brain. A similar distribution pattern was observed after subcutaneous administration of 50 mg ['#C]-pentachlorophenol/kg body weight. The concentration of radiolabel in liver remained high 1 week after dosing. These data are similar to those obtained after oral administration of pentachlorophenol. Based on plasma concentrations and clearance rates, the volume of distribution of pentachlorophenol was estimated to be relatively small and corresponded to approximately albumin and volume of extracellular fluid following intravenous injection of a single dose of 2.5 mg/kg to rats (Reigner et al. 1991). Similar results were obtained in mice (Reigner et al. 1992b). Therefore, the study authors concluded that pentachlorophenol distribution is restricted because of extensive plasma protein binding. 2.3.3 Metabolism Results from animal and human studies indicate that pentachlorophenol is not extensively metabolized, as evidenced by a large portion of the administered dose being excreted in urine unchanged in all species studied. Extensive plasma protein binding of pentachlorophenol discussed in Section 2.3.2.2 may account for the low degree of metabolism because protein-bound material is not readily distributed to tissues. However, available human and animal data indicate that metabolism of pentachlorophenol does occur in the liver, and the major pathways are conjugation to form glucuronide and oxidative dechlorination to form TCHQ. A summary of possible metabolic pathways for pentachlorophenol is presented in Figure 2-2. PENTACHLOROPHENOL 60 2. HEALTH EFFECTS FIGURE 2-2. Proposed Metabolic Scheme for Pentachlorophenol URINARY METABOLITES COOH o H H OH Glucuronic 0 Acid H H OH cl Cl OH H URINE -———— cl cl pcp Cl Cl PCP-Glu 5 o SO3H T c 2 cl Cytochrome P450 i 8 Cl Cl 0 Cl pcp-s — ee — — — — ee — — — — COOH Ro H OH Glucuronic 0 H 3 Acid H H OH cl cl cl -— i, cl c 2H TCG TCHQ OH ~ E sc 22 3 2 = se cg oo -_—_ _ _ 5% | _________ H Glucuronic H ¢ of Acid H OH W o x 0 I ov Q x o Cl Cl OH TiicP-S PCP = pentachlorophenol; PCP-Glu = pentachlorophenol- B-glucuronide; PCP-S = pentachlorophenylsulfate; TCHQ = tetrachloro-p-hydroquinone; TCP-Glu = tetrachlorophenol- B-glucuronide; TCP-S = tetrachlorophenylsulfate; TCQ = tetrachloroquinone; Tri CHQ = trichloro-p-hydroquinone; Tri CP-Glu = trichlorophenyl- B-glucuronide; Tri CP-S = trichlorophenylsulfate; Tri CQ = trichloro-p-quinone PENTACHLOROPHENOL 61 2. HEALTH EFFECTS 2.3.3.1 Inhalation Exposure Ahlborg et al. (1974) analyzed urine from two workers employed as spraymen 24 hours after exposure to sodium pentachlorophenate that was presumably via the inhalation route. Both unchanged pentachlorophenol and TCHQ were identified (relative proportions were not specified), but no mention was made regarding the possible presence of glucuronide conjugates. Thus, at least oxidative dechlorination of pentachlorophenol occurs in humans exposed via inhalation. Information regarding metabolism of pentachlorophenol following inhalation exposure in animals is limited. It has been reported that 70-75% of inhaled pentachlorophenol is excreted unchanged in urine following a single exposure in rats, indicating that metabolism occurs only to a small extent (Hoben et al. 1976a). 2.3.3.2 Oral Exposure Oral administration of small doses of pentachlorophenol (0.02-0.31 mg pentachlorophenol/kg) to volunteers resulted in excretion of unchanged pentachlorophenol (78% of administered dose) andpentachlorophenol glucuronide (12% of the administered dose) in urine and feces (Braun et al. 1979; Uhl et al. 1986). No TCHQ was identified. Studies in rats indicate that both metabolic pathways described above were operative following oral administration of pentachlorophenol, but most of the administered dose was excreted unchanged (Ahlborg et al. 1974; Braun et al. 1977; Renner 1989; Renner and Hopfer 1990). The following urinary metabolites were recovered and identified by gas chromatography from female Sprague-Dawley rats dosed with pentachlorophenol (>99% pure) for 28 days: 2,3,4,5-tetrachloro- phenol; 2,3,4,6-tetrachlorophenol; 2,3,5,6-tetrachlorophenol; tetrachlorocatechol; trichloro-1,4- benzenediol; tetrachloro-1,4-benzenediol; tetrachlororesorcinol; trichlorohydroquinone; TCHQ; and traces of trichloro-1,4-benzoquinone and tetrachloro-1,4-benzoquinone. The major metabolite was TCHQ, which was excreted mainly as a glucuronide conjugate (Renner and Hopfer 1990). Based on the urinary metabolites identified, the study authors concluded that the main metabolic pathway for pentachlorophenol in the rat was pentachlorophenol to 2,3,5,6- tetrachlorophenol to TCHQ, with a minor pathway being pentachlorophenol to 2,3,4,6- and PENTACHLOROPHENOL 62 2. HEALTH EFFECTS 2,3,4,5-tetrachlorophenol to trichlorohydroquinone. Pentachlorophenol (conjugated with glucuronic acid and unconjugated) and TCHQ (conjugated with glucuronic acid and unconjugated) were recovered from urine and quantified by high-performance liquid chromatography and confirmed by using capillary gas chromatography from female Sprague- Dawley rats dosed with pentachlorophenol (>99% pure) for 28 days (Renner and Hopfer 1990). Unconjugated pentachlorophenol accounted for 36-58% of pentachlorophenol recovered, and 10-19% of the TCHQ excreted was unconjugated. Concentrations of both pentachlorophenol and TCHQ in urine fell to negligible amounts within 1 week after cessation of treatment. The study authors concluded that conjugation of pentachlorophenol with glucuronide and its subsequent metabolism to TCHQ in rats results in more rapid excretion than in species that excrete unchanged pentachlorophenol (e.g., monkey) (see discussion below). In other studies in rats, 48% of the 100 mg [4C]-pentachlorophenol/kg administered orally to rats was recovered as unchanged pentachlorophenol in urine, 10% was TCHQ, and 6% was penta- chlorophenol-glucuronide. No TCHQ-glucuronide was detected (Braun et al. 1977). Similar results were obtained in rats and mice when a single dose of 25 mg ['4C]-pentachlorophenol was administered by gavage, except that TCHQ conjugates (not positively identified as glucuronides) were identified in urine (Ahlborg et al. 1974). These investigators found that 41-43% of the administered radiolabel was recovered in the urine as unchanged pentachlorophenol in rats and mice, 5% as TCHQ in rats, and 24% as TCHQ in mice. An unspecified proportion of radioactivity was found in urine as conjugated pentachlorophenol and TCHQ, but it could not be determined whether these were glucuronide conjugates. Other investigators have reported results in rats that differ from those of Braun et al. (1977). Approximately 60% of a 2.5-mg/kg dose of pentachlorophenol was recovered in the urine of Sprague-Dawley rats after 72 hours, mostly as conjugated pentachlorophenol and TCHQ, with only 5.3+0.2% of the dose recovered as unchanged pentachlorophenol (Reigner et al. 1991). Treatment of urine with sulfuric acid indicated that sulfate conjugates of pentachlorophenol and TCHQ accounted for about 90% of conjugated pentachlorophenol and TCHQ (glucuronide conjugates reported by Braun et al. [1977]). Metabolites and unchanged pentachlorophenol in feces accounted for 10% of the administered dose. It has been demonstrated that the monkey differs from the rat and mouse in that virtually all radioactivity recovered in urine following oral administration of 10 mg ['*C]-pentachlorophenol/kg PENTACHLOROPHENOL 63 2. HEALTH EFFECTS was associated with pentachlorophenol; no TCHQ or glucuronide conjugates were identified (Braun and Sauerhoff 1976). These data suggest that pentachlorophenol is not metabolized to any great degree by the monkey. 2.3.3.3 Dermal Exposure No studies were located regarding metabolism in humans or animals after dermal exposure to pentachlorophenol. 2.3.3.4 Other Routes of Exposure Results of studies in rats and mice indicate that metabolism of pentachlorophenol following intraperitoneal injection is similar to that observed following oral exposure (Ahlborg et al. 1978; Jakobson and Yllner 1971). In vitro studies in both human and rat liver homogenates clearly demonstrate that pentachlorophenol is converted to TCHQ (Juhl et al. 1985). The rate of pentachlorophenol-glucuronide conjugation in human liver microsomes is reported to be one-third of that found in rat liver microsomes (Lilienblum 1985). Although phenobarbital enhanced dechlorination of pentachlorophenol, phenobarbital and 3-methylcholanthrene (another microsomal enzyme inducer) had little effect on the conjugation reaction in rat liver microsomes (Ahlborg et al. 1978). This indicated that the extent of glucuronide conjugation was governed by factors other than phenobarbital- and 3-methylcholanthrene-inducible microsomal enzyme activity. It has been proposed that accumulation of pentachlorophenol by lipid-containing tissues seen in vitro is due to conjugation with fatty acids (Leighty and Fentiman 1982). These investigators reported that pentachlorophenol conjugated with palmitic acid in an in vitro rat liver coenzyme A fortified microsomal system. This ester is also found in human fat (Ansari et al. 1985). The mechanism by which the palmitoyl-pentachlorophenol is formed in human fat has yet to be determined. The presence of this ester in human fat demonstrates that xenobiotics such as pentachlorophenol can be made more lipophilic and stored in the fat of humans rather than excreted by the kidneys, thereby providing a potential reservoir of toxin that could be released at a later time. PENTACHLOROPHENOL 64 2. HEALTH EFFECTS Binding of pentachlorophenol to specific components of liver cells can affect its metabolic fate or that of other xenobiotics and ultimately regulate the manifestation of toxic effects. Pentachloro- phenol distributes to the microsomal fraction of the liver at concentrations that are six times those found in mitochondria. Levels in cytosol are three times those found in mitochondria. Binding in mitochondria can cause an uncoupling of oxidative phosphorylation. Therefore, its presence in microsomes can cause a malfunction in the microsomal detoxication process by affecting electron transport processes and thus inhibiting its own metabolism (Arrhenius et al. 1977). This theory provides an explanation for the relative lack of pentachlorophenol metabolism seen in all species studied. Another possible explanation is that extensive plasma binding of pentachlorophenol limits distribution of pentachlorophenol to the liver for subsequent biotransformation. In either case, any perturbation that increases the level of free circulating pentachlorophenol may result in enhanced toxicity as well as an increased rate of biotransformation and elimination. For individuals living in close proximity to areas of potentially high pentachlorophenol exposure, concomitant exposure to chemicals or intentional ingestion of drugs that compete with penta- chlorophenol for protein binding may enhance pentachlorophenol-induced toxicity. 2.3.4 Excretion 2.3.4.1 Inhalation Exposure The available information regarding pentachlorophenol excretion following inhalation exposure in humans comes predominantly from occupational case studies. Data obtained by Bevenue et al. (1967) from measuring urinary levels of pentachlorophenol in residents of Honolulu (some with a history of occupational exposure to pentachlorophenol) indicated that elimination was biphasic, with urinary pentachlorophenol levels decreasing approximately 35% per day in the first 2 days. Urinary levels of pentachlorophenol measured in wood-treatment workers prior to, during, and after vacation implied a urinary half-life of elimination of 19-20 days following inhalation exposure (Begley et al. 1977). The results of studies conducted by Casarett et al. (1969) in occupationally exposed humans suggest that pentachlorophenol excretion kinetics differ between single high-level and chronic low-level exposure. Urinary half-lives of approximately 10 hours were displayed by two subjects following a 45-minute inhalation exposure resulting from painting household materials in an enclosed area, whereas urine pentachlorophenol levels in exposed workers decreased only by 60-80% when the workers were absent from work PENTACHLOROPHENOL 65 2. HEALTH EFFECTS for up to 18 days. The authors hypothesized that slower elimination of pentachlorophenol in the chronic situation may be the result of the establishment of an equilibrium between lung, plasma proteins, urine, and tissue depots. A group of seven saw mill workers (6 males and 1 female) exposed to a sodium chlorophenolate wood preserving product containing 3% pentachlorophenol were monitored for serum and urinary concentrations of pentachlorophenol (as well as other chlorophenols) throughout a wood treatment season of approximately 7 months and an additional 171 days after the termination of exposure for the season (Pekari et al. 1991). Maximal pentachlorophenol urine concentrations after the period of exposure were 0.2-0.9 pmol/L. Approximately 76% of the pentachlorophenol in urine was conjugated. The elimination rate constant in these workers using a one-compartment model was 0.044+0.018/day with a corresponding half-life of 16 days for pentachlorophenol. The minimal urinary clearance for pentachlorophenol was 0.2 mL/minute and varied with urinary flow. These results indicate that pentachlorophenol is eliminated in the urine, primarily in the conjugated form. The study authors noted that the relatively high concentrations of pentachlorophenol found in the serum (23%) as compared to the low percentage of pentachlorophenol in the technical product (3%) indicates that pentachlorophenol accumulates in the serum, in accordance with its relatively long half-time (16 days as compared to 18 hours and 4.2 days for tri- and tetrachlorophenol, respectively). Breathing zone measurements of concentration of airborne contamination compared to quantitative urine measurements would greatly improve the quality of the study. Excretion of pentachlorophenol following inhalation exposure in animals has not been well documented. The elimination half-life of pentachlorophenol following a single 20-minute inhalation exposure to 5.7 mg [4C]-pentachlorophenol/kg was 24 hours (Hoben et al. 1976c¢). Pentachlorophenol does not undergo appreciable biotransformation as most of the inhaled dose was found to be eliminated unchanged in the urine. The authors of this study also reported that repeated (five) exposures increased urinary output of pentachlorophenol. These results are not inconsistent with those of Casarett et al. (1969). Elimination of many toxicants from high body burdens follows first-order kinetics initially, but the pattern of elimination becomes much more complex as lower body burdens are attained. Accumulation with repeated exposure will occur if rate of absorption exceeds rate of elimination, irrespective of excretion kinetics or tissue storage. PENTACHLOROPHENOL 66 2. HEALTH EFFECTS 2.3.4.2 Oral Exposure Studies investigating excretion of pentachlorophenol by humans following ingestion of 0.016-0.31 mg pentachlorophenol/kg have yielded conflicting results. Uhl et al. (1986) found that pentachlorophenol was excreted slowly, displaying an elimination half-life in both blood and urine of 14 days and a renal clearance of 0.07 mL/minute following ingestion of 0.016-0.31 mg penta- chlorophenol/kg in ethanol by volunteers. The authors concluded that slow elimination could be attributed to extensive plasma protein binding and tubular reabsorption. When Braun et al. (1979) studied excretion kinetics of pentachlorophenol (as the sodium salt) in volunteers who ingested 0.1 mg pentachlorophenol/kg, they found that the half-life of elimination was 30.2 hours from plasma and 33.1 hours from urine for pentachlorophenol, and 12.7 hours from urine for the glucuronide conjugate. Approximately 74% of the administered dose was eliminated in urine as pentachlorophenol and 12% as pentachlorophenol-glucuronide within 168 hours postingestion, and 4% was recovered as pentachlorophenol and pentachlorophenol- glucuronide in feces. These investigators concluded that pentachlorophenol elimination in humans followed first-order kinetics with enterohepatic recirculation following oral exposure. One possible explanation for the different half-lives observed in the Uhl et al. (1986) and the Braun et al. (1979) studies is the different dosing procedures employed. Subjects in the Uhl et al. (1986) study were reported to have ingested pentachlorophenol "without restriction of diet," while Braun et al. (1979) reported that "food was withheld 8 hours before and 1 hour after ingestion of the dose." Dispersion in gut contents may have slowed absorption in the Uhl et al. (1986) subjects, while absorption of the full dose occurred over a much shorter interval in the Braun et al. (1979) subjects, thus accounting for the different half-lives observed. Other explanations for the differences observed between the two studies include the fact that sodium pentachlorophenate was used for the Braun et al. (1979) study and pentachlorophenol in ethanol was used for the Uhl et al. (1986) study, and the vehicle used in the Uhl et al. (1986) study (ethanol) may have altered the solubility of pentachlorophenol. Elimination of pentachlorophenol in rats following oral exposure was shown to be rapid and biphasic, with urine being the major route of excretion (Braun et al. 1977). The authors of this study reported that within 8-9 days, 80% of the radioactivity from the single oral administration of 10 mg [4C]-pentachlorophenol/kg to rats was recovered in urine and 19% in feces; 64% was PENTACHLOROPHENOL 67 2. HEALTH EFFECTS detected in urine and 34% in feces following single oral administration of 100 mg [4C]-penta- chlorophenol/kg. Elimination half-lives were 17 and 13 hours for the first phase and 40 and 30 hours for the second phase in low-dose males and females, respectively. Ninety percent of the radioactivity was eliminated in the first phase. High-dose males exhibited elimination half-lives of 13 and 121 hours for the first and second phases, respectively. High-dose females exhibited first-order kinetics with a half-life of 27 hours. No explanation was offered for the difference in kinetics seen in high-dose females. These data indicate that (1) the rate of elimination in the slow phase only and the relative distribution of radioactivity in feces varied linearly with increasing dose, (2) females eliminated pentachlorophenol faster than males, and (3) plasma binding and hepatic retention could account for the prolonged second phase of elimination. Different results were reported in rats administered single doses of 37-41 mg ['4C]-pentachloro- phenol/kg (Larsen et al. 1972). While the half-lives of rapid phases of elimination were comparable, Larsen et al. (1972) reported a half-life of 102 days for the second phase. However, these data are questionable because Larsen et al. (1972) did not obtain 100% recovery in urine and assumed that fecal excretion was constant. Therefore, they only reported a total fecal excretion value after 10 days. Results similar to those obtained by Braun et al. (1977) were reported by Reigner et al. (1991, 1992b) with respect to urinary and fecal elimination of pentachlorophenol following single-dose exposure in rats and mice. In the Reigner et al. studies, 810% of the administered dose (2.5 and 15 mg/kg, respectively, for rats and mice) of pentachlorophenol was recovered in the feces. Therefore, biliary excretion must play some role in elimination of pentachlorophenol. Elimination of pentachlorophenol by monkeys was slow and followed first-order kinetics. Braun and Sauerhoff (1976) orally administered single doses of 10 mg [4C]-pentachlorophenol/kg to monkeys and monitored excretion of radioactivity for up to 360 hours after administration. They found that 10-20% of administered radioactivity was steadily excreted in the feces, attesting to a relatively high degree of biliary secretion. Urinary pentachlorophenol accounted for 70-80% of the administered radiolabel. The half-life of elimination was 40.8 hours in males and 92.4 hours in females. The long half-life was attributed to enterohepatic circulation with subsequent biliary secretion. PENTACHLOROPHENOL 68 2. HEALTH EFFECTS The role of enterohepatic circulation and biliary secretion in pentachlorophenol elimination in monkeys was further investigated by measuring the relative extent of excretion of pentachloro- phenol in urine, feces, and bile before and after administration of cholestyramine, a substance that binds phenols (Ballhorn et al. 1981; Rozman et al. 1982). At 30 mg/kg/day, control excretion was 92.3% in urine and 7.7% in feces. Following cholestyramine administration, excretion was 12.1% renal and 86.9% fecal. At 50 mg/kg/day, control excretion was 79.9% renal and 20.1% fecal. Following cholestyramine administration, excretion was 15.4% renal and 84.6% fecal. Total excretion was also increased by cholestyramine administration. Total recovery of administered dose over a 6-day period increased from 26% to 45% at the low dose and from 15% to 31% at the high dose (Ballhorn et al. 1981). In a follow-up study, cholestyramine treatment reduced urinary excretion of pentachlorophenol from 35% to 5% of the administered dose and increased fecal excretion from 3% to 54% of the administered dose. The increase in fecal excretion induced by cholestyramine exceeded the decrease in urinary excretion. Total excretion increased by 40%. Seventy percent was excreted in bile during the control period, and 52% was excreted in bile after cholestyramine treatment (Rozman et al. 1982). The number of animals used in the studies described above was too small to permit statistical analysis. Even so, the following conclusions can be drawn: (1) In untreated monkeys, oral absorption of pentachlorophenol was followed by elimination via bile into the duodenum, reabsorption in the small intestine, and enterohepatic circulation and excretion, predominantly via the kidney. (2) Cholestyramine, which binds phenols, interrupted enterohepatic circulation by binding penta- chlorophenol and/or its metabolites, resulting in predominantly fecal excretion. (3) Total excretion was increased after cholestyramine treatment, suggesting that it reduced the half-life of pentachlorophenol in the monkey by enhancing its elimination from the body. (4) Cholestyramine increased elimination of pentachlorophenol by sequestering it from enterohepatic circulation. PENTACHLOROPHENOL 69 2. HEALTH EFFECTS Excretion data in animals indicate that the kinetics of pentachlorophenol elimination in humans following oral exposure is similar to that seen in monkeys in that they are first order. However, elimination of pentachlorophenol is dependent on the ratio of dissociated and undissociated forms of the chemical, and this ratio is a function of pH and independent of the form originally ingested. Thus, it is difficult to predict the rate and extent of pentachlorophenol excretion following oral exposure to pentachlorophenol in humans based solely on animal data, given the information that does exist for humans. 2.3.4.3 Dermal Exposure No studies were located regarding excretion in humans or animals after dermal exposure to penta- chlorophenol. 2.3.4.4 Other Routes of Exposure Kinetics of elimination of pentachlorophenol in rats following a single intravenous injection (Reigner et al. 1991) differ from those reported by Braun et al. (1977) following oral exposure. In the Reigner et al. (1991) study, the clearance rate of pentachlorophenol from plasma was 0.026+0.003 L/hour/kg. Elimination of pentachlorophenol from plasma was biphasic and fit a two-compartment model, with the half-life for the first phase being 0.67+0.46 hours and the half- life for the second phase being 7.11+0.87 hours. Most of the pentachlorophenol was eliminated during the second phase. However, routes of excretion and main metabolites recovered in urine and feces were similar to those seen by these same investigators after oral administration (Reigner et al. 1991). The study authors proposed that specificity of the analytical methodology is one possible explanation for the difference in elimination kinetics seen between their study and the study by Braun et al. (1977), who instead of taking multiple blood samples from the same animal, killed two animals at different times to get the kinetic profile. Use of pooled data such as this may have provided inaccurate data for modeling. 2.3.5 Mechanisms of Action Pentachlorophenol is a nonpolar, lipophilic substance. While the exact mechanism of absorption is not known, it can be assumed that because of its lipophilicity it can easily cross cell membranes PENTACHLOROPHENOL 70 2. HEALTH EFFECTS and be absorbed in lungs, gastrointestinal tract, and skin. Toxicokinetic studies in animals and humans demonstrate this to be the case (see Section 2.3.1). Binding of pentachlorophenol to plasma proteins plays a role in the distribution of pentachloro- phenol (Braun et al. 1977). It has been demonstrated, using an in vitro diafiltration technique (Braun et al. 1977), that 95% of the pentachlorophenol in plasma is protein bound. Extensive plasma protein binding of pentachlorophenol may account for the low degree of metabolism seen with this compound (most pentachlorophenol is excreted unchanged) because protein-bound material is not readily distributed to tissues where it can be metabolized. It is widely believed that pentachlorophenol exerts its toxic effects by uncoupling mitochondrial oxidative phosphorylation, thereby causing accelerated aerobic metabolism and increased heat production. Pentachlorophenol has been found to bind to purified rat liver mitochondrial protein. This may induce conformational changes in enzymes involved in oxidative phosphorylation (Weinbach and Garbus 1965). The pattern of pentachlorophenol-induced toxicity often seen in humans and animals supports this proposed mechanism of action. A young worker who died following 3 weeks of exposure to pentachlorophenol dust in a chemical plant was found to have cerebral edema and fatty degeneration of liver and lungs at necropsy (Gray et al. 1985). The study authors concluded that these clinical findings are consistent with a hypermetabolic state resulting from a derangement of aerobic metabolism and characterized by hyperthermia, which can lead to tachycardia, tachypnea, hyperemia, diaphoresis, and metabolic acidosis. This is usually followed by death and rapid, profound rigor mortis. Toxicity resulting from uncoupling of oxidative phosphorylation was generally seen prior to death in animals acutely exposed to penta- chlorophenol. These included accelerated respiration, hyperemia, cardiac and muscular collapse, asphyxial convulsions, death, and rapid rigor mortis (St. Omer and Gadusek 1987). The ultrastructural changes observed in mitochondria from liver cells of rats treated with technical grade pentachlorophenol for 15 days are consistent with uncoupling of oxidative phosphorylation (Fleischer et al. 1980). The cell membrane is apparently the site of action for pentachlorophenol. Lipid bilayers of purified and total cell membranes have been reported to destabilize following sublethal penta- chlorophenol treatment (Duxbury and Thompson 1987). This was evidenced by a 50% decrease in bulk lipid fluidity attributable to disruption of the bilayer by pentachlorophenol. These authors PENTACHLOROPHENOL 71 2. HEALTH EFFECTS also found that pentachlorophenol partitions into the hydrophobic interior of the bilayer. Other membrane changes observed by these investigators included a decrease in phospholipid phosphate levels that they believe was a result of a selective chemical effect on phospholipase C. However, the authors concluded that this was only a sublethal effect since the cells remained viable. In another investigation of the physicochemical basis of pentachlorophenol membrane effects, membrane toxicity was associated with the pentachlorophenol-induced change in hydrogen ion permeability of the membrane lipid matrix (Smejtek 1987). The onset of toxic effects was correlated with the loss of membrane electrical resistance and a measurable amount of penta- chlorophenol binding to the membrane. Studies described above indicate that pentachlorophenol is a metabolic poison that exerts its effects by disrupting membrane function. This effect could conceivably occur throughout the body and could therefore explain the wide range of toxic effects associated with pentachloro- phenol, including the uncoupling of oxidative phosphorylation. Studies in animals have shown that acute (single-dose, intraperitoneal injection) pentachloro- phenol administration causes a marked, statistically significant decrease in serum total thyroxin levels in rats (van Raaij et al. 1991b). This decrease peaked 6-24 hours after administration, and thyroxin levels slowly returned to control values within 96 hours after administration. Further in vitro studies by these investigators revealed that the likely mechanism of action for this anti- thyroid effect was competition for serum protein thyroxin binding sites (van Raaij et al. 1991a). 2.4 RELEVANCE TO PUBLIC HEALTH Pentachlorophenol was, in the past, one of the most heavily used pesticides in the United States but is now regulated as a restricted-use pesticide. The compound is found in all environmental media as a result of its past widespread use. In addition, a number of other environmental contaminants, including hexachlorobenzene, pentachlorobenzene, pentachloronitrobenzene, and hexachlorocyclohexane isomers, are known to be metabolized to pentachlorophenol. Current releases of pentachlorophenol to the environment are more limited than historical releases of the compound as a result of changing use patterns (e.g., phase-out of slimicide use in cooling water towers) and waste treatment practices (e.g., closing of on-site evaporation ponds at wood- PENTACHLOROPHENOL 72 2. HEALTH EFFECTS treatment facilities). Ambient levels of pentachlorophenol are reported to be 0.1-10 pg/L in surface water and 0.07-12 pg/L in drinking water. Intake of pentachlorophenol via ingestion of contaminated food has been estimated to be 0.2-59 ng/kg/day. Reports of human exposure to pentachlorophenol come primarily from occupational exposure by inhalation of contaminated workplace air and dermal contact with the compound or treated wood products. OSHA, ACGIH, and NIOSH have all set occupational exposure time-weighted-average limits for 8-hour/day, 40-hour/week, workplace exposure of 0.5 mg/m’. The general population may also be exposed by ingestion of contaminated drinking water, ingestion of contaminated foods and soil, or dermal contact with contaminated soil or treated wood products. Exposure through domestic use is less likely because the use of pentachlorophenol in the home is banned. Since pentachlorophenol is no longer employed in the treatment of wood products used in new residences and agricultural buildings, future indoor air exposure to this compound from these sources should be minimal. Absorption of pentachlorophenol occurs predominantly through the skin by direct contact with treated wood surfaces and/or inhalation, although ingestion of contaminated food and water or exposure at chemical spills and hazardous waste sites is also possible. In past decades, pentachlorophenol has been widely detected in human urine, blood, and adipose tissue from members of the general North American population. Evidence was found in the reviewed literature that pentachlorophenol is toxic to both humans and experimental animals. The major target organs for both humans and animals are the liver and the kidney. The central nervous system (following acute-duration exposure) and the immune system in both humans and animals also appear to be affected by pentachlorophenol exposure, generally as a result of hyperthermia induced by the uncoupling of oxidative phosphorylation (central nervous system), or as a result of the presence of impurities such as chlorinated dibenzo-p-dioxins (immune system effects). Limited data in animals suggest that pentachlorophenol may adversely affect the survival of offspring exposed in utero, but information available in humans is not adequate to support this finding. No information is available on potential developmental toxicity of pentachlorophenol in humans, but studies in animals indicate that both technical grade and pure compound are not teratogenic in experimental animals. However, pentachlorophenol, in adequate dosage, is embryo- and fetotoxic in animals. Sufficient evidence exists from animal studies to suggest that pentachlorophenol may cause cancer in humans even though there are no supporting human data to substantiate this possibility. PENTACHLOROPHENOL 73 2. HEALTH EFFECTS Humans are generally exposed to technical grade pentachlorophenol which usually contains such toxic impurities as polychlorinated dibenzo-p-dioxins and dibenzofurans (see Table 2-2). Animal studies with both technical and purified pentachlorophenol have demonstrated that many, but not all, of the toxic effects attributed to pentachlorophenol were actually due to the impurities. Only those effects that were truly a result of pentachlorophenol exposure will be discussed in detail in this section. Because human exposure is to technical grade pentachlorophenol and because ATSDR’s intent is to protect human health, special reference is made to those adverse effects seen in humans that are believed to be a result of the contaminants. Many studies discussed in previous sections described toxic effects associated with sodium pentachlorophenate, the water-soluble sodium salt of the nonpolar, relatively water-insoluble pentachlorophenol. Direct comparisons were not made between the two forms in these studies, but it would appear that they exhibit similar toxic properties, although their toxicokinetics differ. Minimal Risk Levels for Pentachlorophenol Inhalation MRLs Inhalation MRLs for acute, intermediate, or chronic exposure have not been calculated. While target organs have been identified in humans following inhalation exposure to technical grade pentachlorophenol, the exposure levels at which these effects occur have not been quantified. No data exist on the toxicity of pentachlorophenol following inhalation exposure in animals from which MRLs could be developed. Oral MRLs e For acute oral exposure, an MRL of 0.005 mg/kg/day has been derived for pentachlorophenol. This MRL was based on a LOAEL of 5 mg/kg/day for delayed ossification of the skull in rat pups when the dams were given pure pentachlorophenol by corn oil gavage on gestation days 6 through 15 (Schwetz et al. 1974). Other skeletal anomalies (including lumbar spurs and supernumerary ribs, vertebrae, and sternebrae, were observed with exposure to pure or technical grade pentachlorophenol at higher doses. PENTACHLOROPHENOL 74 2. HEALTH EFFECTS ® For intermediate oral exposure, an MRL of 0.001 has been derived for pentachlorophenol. This MRL was based on a LOAEL of 1.2 mg/kg/day for increases in serum enzymes levels (alkaline phosphatase in female rats and SGPT in male rats) that may be indicative of hepatotoxicity. Relative liver weights were increased in females at doses of 2.5 mg/kg/day; centrilobular vacuolization was also observed at this dose (Knudsen et al. 1974). Hepatotoxicity has been observed in other studies in animals at comparable or slightly higher doses using both pure (Greichus et al. 1979; Kimbrough and Linder 1978) and technical grade (Kerkvliet et al. 1982, 1985a, 1985b; Kimbrough and Linder 1978; Knudsen et al. 1974; Nishimura et al. 1980) pentachlorophenol. Hepatotoxicity has also been observed in rats (Schwetz et al. 1978) and mice (NTP 1989) chronically exposed to pentachlorophenol. A chronic oral MRL was not calculated because human exposure levels associated with toxic effects are not well quantified following chronic oral exposure, and because the only data available on the noncarcinogenic effects of pentachlorophenol in animals are from studies using technical grade pentachlorophenol that identified LOAELSs that were higher than that used to calculate the intermediate oral MRL. Death. Fatal exposures to pentachlorophenol in humans are associated with hyperthermia which can induce a wide range of manifestations (see discussion above) that include anorexia, fatigue, thirst, high fever, profuse sweating, abdominal symptoms, and severe spasms (Bergner et al. 1956; Gordon 1956; Gray et al. 1987; Menon 1958). This generalized spectrum of toxicity supports the metabolic mechanism of action discussed in Section 2.3.5. Death in animals was preceded by symptoms similar to those described for humans which included fever, increased respiration and heart rate, hyperglycemia and glycosuria, hyperperistalsis, decreased urinary output, coma, cardiovascular and respiratory depression, muscular collapse, terminal asphyxial convulsions, death, and rapid, profound rigor mortis (Deichmann et al. 1942). These signs were similar across all routes of exposure. The lethality of pentachlorophenol was greatly enhanced when it was administered in a fuel or corn oil vehicle (see Table 2-1). Absorption of chemicals such as pentachlorophenol that have substantial lipid solubility across skin and mucous membranes is increased by the presence of hydrocarbon solvents. The greater toxicity of pentachlorophenol when dissolved in hydrocarbon PENTACHLOROPHENOL 75 2. HEALTH EFFECTS solvents may be due partly or entirely to more efficient absorption of pure pentachlorophenol. Since the pentachlorophenol found at hazardous waste sites is often formulated in hydrocarbons such as those present in fuel oil, this enhanced toxicity seen in animals may have important implications for the health of humans exposed to pentachlorophenol-hydrocarbon formulations. Systemic Effects Respiratory Effects. Upper respiratory tract inflammation and bronchitis have been noted in workers chronically exposed to high levels of commercial pentachlorophenol that contained numerous contaminants (Baader and Bauer 1951; Klemmer et al. 1980). No inhalation toxicity studies have been conducted in animals with pure pentachlorophenol to determine whether this effect is a result of pentachlorophenol or its contaminants or other substances to which the workers were concurrently exposed. Therefore, the relevance of this effect for humans living in the vicinity of pentachlorophenol-contaminated hazardous waste sites is not known, but it is unlikely that the airborne concentrations of pentachlorophenol at these sites are comparable to those shown to cause respiratory effects in the occupational setting since pentachlorophenol is relatively nonvolatile. Hematological Effects. Various hematological disorders, including aplastic anemia, pure red cell aplasia, and hemolytic anemia, presumably due to exposure to pentachlorophenol, have been reported in humans (Hassan et al. 1985; Roberts 1963, 1981, 1990; Rugman and Cosstick 1990). The mechanism for these adverse hematological effects may be a direct action on the blood cell- forming tissue. An indirect action via the uncoupling of oxidative phosphorylation is unlikely since no signs of hyperthermia were observed in these cases (Roberts 1981, 1990). Hassan et al. (1985) postulated that the mechanism for pentachlorophenol-induced anemia involves penta- chlorophenol interference with adenosine triphosphate (ATP) formation, leading to hemolysis, as cells are no longer able to maintain osmotic equilibrium across the cell membrane. In vitro studies in human erythrocytes demonstrated that pentachlorophenol binds directly to the erythrocyte membrane, and this interaction with the membrane causes hemolysis (Igisu 1993). Alternatively, it has been suggested that aplastic anemia associated with exposure to organochlorine pesticides, such as pentachlorophenol, may be the result of an autoimmune response, abnormal metabolism leading to excessive accumulation of pentachlorophenol, and/or a genetic predisposition to hematopoietic stem cell abnormality that is exacerbated by exposure to PENTACHLOROPHENOL 76 2. HEALTH EFFECTS pentachlorophenol (Rugman and Cosstick 1990). While adverse hematological effects have been observed in animals exposed to technical grade pentachlorophenol, they were generally not observed when animals were administered pure pentachlorophenol (Greichus et al. 1979; Johnson ct al. 1973). Therefore, it is likely that the hematotoxicity observed in humans exposed to pentachlorophenol may be the result, in part, of the contaminants present in pentachlorophenol. However, given the adverse hematological effects observed in humans exposed to pentachlorophenol, it may be prudent to assume that significant exposure to technical grade pentachlorophenol in the environment, at hazardous waste sites, and occupationally may result in hematotoxicity. Hepatic Effects. Hepatic toxicity in humans, as manifested by elevated serum SGOT and SGPT levels, enlarged livers, fatty infiltration of the liver, and centrilobular congestion and degeneration, was seen following fatal and nonfatal exposures to pentachlorophenol (Armstrong et al. 1969; Bergner et al. 1965; Gordon 1956; Gray et al. 1985; Klemmer 1972; Robson et al. 1969). Contaminants of the technical grade pentachlorophenol may be responsible for some of this damage. In animal experiments that compared the hepatic toxicity of equal doses of technical and purified pentachlorophenol, the effects associated with the purified preparation were much less severe than those seen with the technical grades in most cases. Adverse liver effects seen in animals treated with purified pentachlorophenol included increased liver weight, hepatocellular cloudy swelling, enlargement and vacuolization, pigmentation, mild-to-moderate multifocal necrosis, slight increases in liver enzyme activity, and induction of hepatic MFO activity (Greichus et al. 1979; Johnson et al. 1973; Kerkvliet et al. 1982; Kimbrough and Linder 1978; Nishimura et al. 1980; NTP 1989; Schwetz et al. 1978). Often, biochemical or gross changes were not accompanied by histopathologic changes. Though the animal studies were only conducted via the oral or intraperitoneal routes of exposure, evidence from acute studies indicates that the toxic effects of pentachlorophenol are similar regardless of exposure route (Deichmann et al. 1942). While it is evident that pure pentachlorophenol does possess some degree of hepatic toxicity, the hepatotoxic response to the technical grade appears to be more severe. Therefore, hepatic effects seen in humans following occupational or other types of high-level exposure most likely result from a combination of exposure to pentachlorophenol and the impurities present in the technical grade. Because adverse hepatic effects have only been reported in humans exposed to high levels of PENTACHLOROPHENOL 77 2. HEALTH EFFECTS technical grade pentachlorophenol. it is not likely that hepatic effects will occur in individuals living in the vicinity of hazardous waste sites contaminated with pentachlorophenol. Renal Effects. Pure pentachlorophenol exerts a minor toxic effect on the kidneys. This conclusion is based on the observations that little or no consistent difference was seen between technical grade and purified pentachlorophenol with regard to severity of renal effects in animals, and that renal effects observed in both humans and animals are mild and transient. Evidence of renal dysfunction, such as impaired glomerular filtration and tubular function and mild tubular degeneration, has been reported in cases of human exposure to pentachlorophenol (Begley et al. 1977; Bergner et al. 1965; Chapman and Robson 1965). Begley et al. (1977) observed that these effects were reversible following removal from the area of chemical exposure. The most frequently reported toxic effects seen in the kidneys of rats administered pentachloro- phenol include increased enzyme levels, organ weights, and pigmentation of renal cells. Often, the effects observed are compound related but not dose related or are only seen in one sex (Kimbrough and Linder 1978). Organ weight changes are usually not accompanied by histopathological changes. The increase in kidney weight was probably due to edema linked to metabolic disturbances attributed to pentachlorophenol (see previous discussion) such as impaired acid-base balance, impaired glomerular filtration, and uncoupling of oxidative phosphorylation. Biochemical changes indicative of renal toxicity (e.g., increased blood urea nitrogen, loss of proximal tubular alkaline phosphatase activity) have been observed in pentachlorophenol-treated animals (Greichus et al. 1979; Nishimura et al. 1980). These changes were reversible, similar to what has been observed in humans. The biological significance of these apparently reversible renal effects with regard to long-term toxicity (i.e., in individuals living in the vicinity of hazardous waste sites contaminated with pentachlorophenol that are exposed over long periods of time) is not certain. Dermal/Ocular Effects. Dusts from pentachlorophenol and its sodium salt are particularly irritating to the eyes and nose in concentrations greater than 1 mg/m’ (0.09 ppm) (ACGIH 1990). Prolonged occupational exposure (both inhalation and, to a greater extent, dermal) to technical pentachlorophenol has been reported to be associated with chloracne (O'Malley et al. 1990; PENTACHLOROPHENOL 78 2. HEALTH EFFECTS Seghal and Ghorpade 1983), and other severe skin lesions (pemphigus vulgaris and chronic urticaria) resulting from nonoccupational chronic dermal exposure to wood treated with pentachlorophenol (Lambert et al. 1986). In all cases, these skin lesions were most likely the result of exposure to the pentachlorophenol contaminants, chlorinated dibenzo-p-dioxins and dibenzofurans. There are no data available in animals to determine whether pure pentachlorophenol induces the skin lesions described above. However, because humans living near hazardous waste sites are likely to be exposed to technical grade pentachlorophenol, these individuals may be at risk for adverse dermal effects. Other Systemic Effects. Adrenocortical dysfunction has been linked to reproductive disorders in women with long-term exposure to pentachlorophenol-containing wood preservatives (Gerhard et al. 1991). Concurrent exposures to other chemicals and lack of control for other confounding factors discredit this report. Studies in animals have shown that acute (single-dose, intraperitoneal injection) pentachlorophenol administration causes a marked, statistically significant decrease in serum total thyroxin levels in rats (van Raaij et al. 1991b). This decrease peaked 6-24 hours after administration, and thyroxin levels slowly returned to control values within 96 hours after administration. Further in vitro studies by these investigators revealed that the likely mechanism of action for this anti-thyroid effect was competition for serum protein thyroxin binding sites (van Raaij et al. 1991a). Definitive conclusions regarding the effect of pentachlorophenol on thyroid function with respect to relevance to human health cannot be drawn based on these results. Immunological Effects. The two skin lesions (believed to have an immunological etiology) discussed earlier in this section in "Dermal/Ocular Effects" and the study by Gerhard et al. (1991) provide evidence that prolonged exposure to commercial pentachlorophenol-containing wood preservatives may be associated with reproductive disorders that are secondary to immunologic and/or endocrine dysfunction. This is the only evidence for pentachlorophenol-induced immunotoxicity in humans. The available animal data indicate that technical grade pentachloro- phenol affects a wide range of immune functions, such as humoral and cellular immunity, susceptibility to tumor induction, and complement activity (Holsapple et al. 1987; Kerkvliet et al. 1982, 1985a, 1985b; White and Anderson 1985). Many of the effects reported may be due to impurities present in technical grade pentachlorophenol. This is supported by results from animal PENTACHLOROPHENOL 79 2. HEALTH EFFECTS studies that compared effects of both technical grade and purified pentachlorophenol on immune function. For example, suppression of in vivo antibody response to SRBC was seen with technical grade but not pure pentachlorophenol (Holsapple et al. 1987; Kerkvliet et al. 1985a); pure penta- chlorophenol had no effect on the ability to resist syngeneic tumor growth (an indication of general immunological surveillance) whereas the technical grade did (Kerkvliet et al. 1982); and complement activity was inhibited only by technical grade pentachlorophenol (White and Anderson 1985). A study conducted by Kerkvliet et al. (1985b) demonstrated that the immunosuppressive effect of technical pentachlorophenol is mediated by Ah-interactive isomers of the contaminants, chlorinated dibenzo-p-dioxins and dibenzofurans. One strain of rats with a high-affinity Ah receptor exhibited a significant compromise in immune function in response to technical pentachlorophenol, whereas another strain with a low-affinity Ah receptor did not respond in this manner. It has previously been shown that the ability of these contaminants to bind to this receptor correlates with their ability to induce P;-450 monooxygenase activity and also with their toxicity. Results of animal studies indicate that pure pentachlorophenol possesses little immunotoxic activity, with the possible exception of increased secondary splenic tumors seen in rats treated with pure pentachlorophenol (see Section 2.2.2.3). However, tests of cell-mediated and humoral immune function conducted with normal human lymphocytes in vitro using both technical grade and pure pentachlorophenol indicate that the pure compound is directly immunotoxic to these cells, affecting both T-cell responses and humoral immune reactivity (Lang and Mueller-Ruchholtz 1991). The study authors speculated that the discrepancy between their results in vitro with human cells and in vivo in animals may be due to rapid metabolism and excretion of pentachlorophenol, but not its contaminants in vivo. As a result, there may be accumulation of immunotoxic metabolites, or direct contact between pentachlorophenol and target immune cells in vitro may not be indicative of organ distribution pattern in vivo. In addition, there may be true species differences with respect to the immunotoxic potential of pentachlorophenol. In any case, the fact that humans are exposed primarily to technical (impure) pentachlorophenol is still reason for concern. Tests for immune competence in humans have not been conducted in cases of pentachlorophenol intoxication. It is difficult to extrapolate the immune function parameters measured in animals to humans. Thus, the biological significance of the immune responses observed in animals to long-term low-level exposure in humans is unknown. PENTACHLOROPHENOL 80 2. HEALTH EFFECTS No clinical signs of toxicity (e.g., increased incidence of infection) of other functional immunological deficiencies were reported to be associated with immunological effects discussed in this section. Therefore, these observed effects are of unknown biological significance. The immunological effects resulting from pentachlorophenol exposure of individuals living in areas surrounding hazardous waste sites are not known and are difficult to predict based solely on the findings discussed above. Neurological Effects. Human case reports of pentachlorophenol exposure suggest central and peripheral nervous system components of toxicity (Chapman and Robson 1965; Gray et al. 1985; Haley 1977; Robson et al. 1969). However, as discussed in Section 2.2.2.4, the neurologic syndrome observed following exposure to pentachlorophenol is probably the direct result of hyperthermia generated by uncoupling of mitochondrial oxidative phosphorylation and not a direct effect on the nervous system. This syndrome can be manifested by lethargy, tachypnea, tachycardia, intermittent delirium, convulsions, cerebral edema, focal swelling of the myelin sheath, and respiratory distress (Chapman and Robson 1965; Gray et al. 1985). Neurochemical changes were also evident after intermediate-duration exposure (Savolainen and Pekari 1979). The peripheral nervous system might also be affected by pentachlorophenol. Axonal conduction and synaptic transmission were irreversibly blocked by pentachlorophenol in an in vitro preparation (Montoya et al. 1988). The relevance of these findings to human exposure is not known since pentachlorophenol has not been reported to cause permanent paralysis, as would be expected from the irreversible changes observed in vitro. No adverse effects on the peripheral nervous system were seen following chronic occupational exposure to pentachlorophenol (Triebig et al. 1987). There was no information in the reviewed literature on the neurotoxic effects of low-level chronic exposure to pentachlorophenol in animals. Reproductive Effects. Aside from a rather limited communication linking long-term exposure to pentachlorophenol-containing wood preservatives to reproductive disorders in women (Gerhard et al. 1991), no information is available on the reproductive toxicity of pentachlorophenol in humans. Studies in animals provide evidence that pentachlorophenol decreases the survival of pups in exposed rats (Schwetz et al. 1974, 1978). Although no data are available in humans, the PENTACHLOROPHENOL 81 2. HEALTH EFFECTS implication of these findings with regard to human exposure is that, at high enough levels of exposure, reduced survival of offspring may occur in women exposed to pentachlorophenol. Developmental Effects. No reports of developmental toxicity following pentachlorophenol exposure in humans were found. The available information from animal studies indicate that pentachlorophenol is not teratogenic. However, it is embryo- and fetotoxic at doses that also induce maternal toxicity (e.g., decreased weight gain) (Larsen et al. 1975). The implications of these findings with regard to human exposure are that, at high enough levels of exposure, adverse effects can occur in the unborn offspring of women exposed to pentachlorophenol. It would appear that the responses observed in animals are due to pure pentachlorophenol since the purified grade elicited effects of even greater severity than the technical grade (Schwetz et al. 1974; Welsh et al. 1987). One explanation for the greater severity of effects seen with pure pentachlorophenol is that the chlorinated dibenzo-p-dioxin and dibenzofuran contaminants of the technical grade are powerful inducers of hepatic microsomal enzymes, many of which are involved in the biotransformation and detoxication of pentachlorophenol. Therefore, some of the toxic effects of pentachlorophenol (such as developmental and reproductive effects) may actually be mitigated by the chlorinated dibenzo-p-dioxin and dibenzofuran contaminants present in the technical grade. Genotoxic Effects. Pentachlorophenol has been tested in several genotoxicity studies. Tables 2-3 and 2-4 report the results of in vivo and in vitro studies, respectively. The available genotoxicity data indicate that pentachlorophenol may have some genotoxic potential, but the evidence for this is not conclusive. It is not mutagenic in bacteria or Drosophila, but positive results were reported in yeast, and it is weakly mutagenic in mice in vivo. Pentachlorophenol produced deoxyribonucleic acid (DNA) damage in repair-deficient bacteria in one test system. A small increase in the frequency of chromosomal aberrations was reported in one study of occupationally exposed workers, while no increase was reported in a second study. Pentachlorophenol exposure of human lymphocytes in vitro produced a weakly positive response. A statistically significant increase in the frequency of chromosomal aberrations was observed in peripheral lymphocytes of workers exposed to pentachlorophenol in a manufacturing plant; the frequency of sister chromatid exchanges was not increased (Bauchinger et al. 1982). In a second TABLE 2-3. Genotoxicity of Pentachlorophenol /n Vivo Species (test system) End point Results Prokaryotic organisms: Salmonella typhimurium (mouse host-mediated assay) Gene mutation S. typhimurium (mouse host-mediated assay) Gene mutation Invertebrate animal cells: Drosophila melanogaster (spermatocytes) Sex-linked recessive — lethal mutation Mammalian cells: Mouse (embryonic cells) Gene mutation (+) Human (occupational exposure /lymphocytes) Chromosomal aberrations (+) Human (occupational exposure /lymphocytes) Chromosomal aberrations — Human (occupational exposure /lymphocytes) Sister chromatid exchange = — Reference Buselmaier et al. 1973 Buselmaier et al. 1973 Fahrig 1974; Fahrig et al. 1978; Vogel and Chandler 1974 Fahrig et al. 1978 Bauchinger et al. 1982 Wyllie et al. 1982 Bauchinger et al. 1982 — = negative result; (+) = weakly positive result S103443 HIV3H 2 JON3IHdJOHOTHOV.LN3d 28 TABLE 2-4. Genotoxicity of Pentachlorophenol In Vitro Results With Without Species (test system) activation activation End point Reference Pentachlorophenol Prokaryotic organisms: JON3HdJOHOTHOVIN3d Salmonella typhimurium S. typhimurium [spot test Escherichia coli WP2 E. coli/spot test Serratia marcescens [spot test Bacillus subtilis [rec- assay E. coli pol A Eukaryotic organisms: Fungi: Saccharomyces cerevisiae MP-1 S. cerevisiae aAeZ S. cerevisiae MP-1/intergenic recombination S. cerevisiae MP-1/intergenic recombination S. cerevisiae Mammalian cells: Human lymphocytes Chinese hamster ovary cells Gene mutation Gene mutation Gene mutation Gene mutation DNA damage DNA damage DNA damage Gene mutation Recombination Recombination Recombination Recombination Chromosomal aberrations DNA damage 3333 3 353 NT NT + (+) Moriya et al. 1983; Simmon et al. 1977; Waters et al. 1982 Andersen et al. 1972; Lemma and Ames 1975 Moriya et al. 1983; Simmon et al. 1977, Waters et al. 1982 Waters et al. 1982 Fahrig 1974 Waters et al. 1982 Waters et al. 1982 Fahrig ct al. 1978 Fahrig 1974 Fahrig et al. 1978 Fahrig ct al. 1978 Waters ct al. 1982 Fahrig 1974 Ehrlich 1990 S103443 HLTV3H 2 £8 TABLE 2-4. Genotoxicity of Pentachlorophenol In Vitro (continued) Results With Without Species (test system) End point activation activation Reference Tetrachlorohydroquinone Mammalian cells: Chinese hamster V79 cells Gene mutation NT + Jansson and Jansson 1991 Chinese hamster ovary cells DNA damage NT + Ehrlich 1990 Chinese hamster V79 cells Micronuclei NT + Jansson and Jansson 1992 Tetrachlorocatechol Mammalian cells: Chinese hamster V79 cells Gene mutation NT —_ Jansson and Jansson 1991 — = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid; NT = not tested S103443 HLIV3aH 2 TONIHJOHOTHOVLNId v8 PENTACHLOROPHENOL 85 2. HEALTH EFFECTS study, no increase in the frequency of chromosomal aberrations was observed in lymphocytes from workers exposed to pentachlorophenol in a wood-treatment plant; this result is not conclusive because of the small number of subjects in the study and a small number of lymphocytes were examined (Wyllie et al. 1975). A slight increase in chromosomal aberrations was observed in human lymphocytes exposed to pentachlorophenol in an in vitro test system, but the statistical significance of the increase cannot be determined based on the data presented in the report (Fahrig 1974). A decrease in cell proliferation was observed when human lymphocytes were treated with 60 mg/L pentachlorophenol in vitro, and concentrations above 90 mg/L were lethal (Ziemsen et al. 1987). Pentachlorophenol has been tested in several in vitro studies. In bacteria, it did not induce gene mutations in assays with or without a metabolic activation system (Andersen et al. 1972; Fahrig 1974; Lemma and Ames 1975; Moriya et al. 1983; Simmon et al. 1977; Waters et al. 1982). Positive results were reported for DNA damage in the Bacillus subtilis rec-assay system (Waters et al. 1982) using the technical grade of pentachlorophenol; negative results were reported in the Escherichia coli polymerase A test (Waters et al. 1982). These results do not necessarily conflict because the two assays have different end points. In yeast, pentachlorophenol induced gene mutations (Fahrig 1974; Fahrig et al. 1978) and genetic recombination (Fahrig et al. 1978; Waters et al. 1982). Pentachlorophenol has been tested in vivo in animals in only one assay. The number of mice with somatic mutations in the mouse spot test was increased after pentachlorophenol administration, and the investigators concluded that the increase was evidence of a weak but definite mutagenic response (Fahrig et al. 1978). In Drosophila, it did not induce sex-linked recessive mutations (Fahrig 1974; Fahrig et al. 1978; Vogel and Chandler 1974). It was not mutagenic in two strains of bacteria when tested in a mouse host-mediated assay system (Buselmaier et al. 1973). Only two studies were found regarding the genotoxic potential of pentachlorophenol metabolites. TCHAQ, but not tetrachlorocatechol, induced a dose-related and significant mutagenic response in Chinese hamster V-79 cells in the absence of exogenous metabolic activation (Jansson and Jansson 1991). TCHQ was also found to exert a severe cytotoxic effect and cause marked DNA damage (i.e., single-strand breaks and/or alkali-labile sites) in Chinese hamster ovary cells; the parent compound was weakly cytotoxic but not genotoxic at comparable levels (Ehrlich 1990). PENTACHLOROPHENOL 86 2. HEALTH EFFECTS Cancer. There is no convincing evidence from epidemiological studies that pentachlorophenol produces cancer in humans. Case reports suggest a possible association between cancer (Hodgkin's disease, soft tissue sarcoma, and acute leukemia) and occupational exposure to technical pentachlorophenol (Fingerhut et al. 1984; Greene et al. 1978; Roberts 1983). However, in all of these cases, concurrent exposure to other toxic substances may have contributed to the effects seen. In addition, these studies are limited by such factors as small sample size, follow-up periods too short to detect an excess cancer risk, mortality due to competing causes of death, and brief exposure periods. There is no convincing evidence from epidemiological studies to indicate that exposure to pentachlorophenol in any form produces cancer in humans (Gilbert et al. 1990; Jippinen et al. 1989; Robinson et al. 1985). Sufficient evidence exists from animal studies to suggest that pentachlorophenol may cause cancer in humans even though there are no supporting human data to substantiate this suggestion. The best evidence comes from a study conducted by the National Toxicology Program (NTP 1989). The study compared the carcinogenic effects of two pentachlorophenol preparations, TG-penta and Dowicide EC-7, by oral administration in the feed to B6C3F, mice for 2 years. EC- 7 contained lower levels of the toxic impurities, dibenzo-p-dioxins and dibenzofurans. The incidence of the following three types of tumors was significantly increased over control values in both studies in one or both sexes: hepatocellular adenomas/carcinomas, adrenal medullary pheochromocytomas (benign and malignant), and hemangiomas/hemangiosarcomas (predominantly in the spleen and liver). Only hepatocellular tumors were seen in carcinogenicity studies of various polychlorinated dibenzo-p-dioxins. It can be concluded that pure pentachlorophenol possesses oncogenic activity in mice. The International Agency for Research on Cancer (IARC 1991) has categorized pentachlorophenol in Group 2B (possibly carcinogenic to humans). EPA has classified pentachlorophenol as a Group B2 substance (probable human carcinogen) (IRIS 1993). 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). PENTACHLOROPHENOL 87 2. HEALTH EFFECTS A biomarker of exposure is a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to pentachlorophenol are discussed in Section 2.5.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by pentachlorophenol are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, Populations That Are Unusually Susceptible. PENTACHLOROPHENOL 88 2. HEALTH EFFECTS 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Pentachlorophenol Since pentachlorophenol is excreted in the urine largely unchanged (Ahlborg et al. 1974; Braun et al. 1979; Larsen et al. 1972; Reigner et al. 1991) and since it can be easily detected and quantified in the urine at concentrations as low as <1 ppb (Chou and Bailey 1986; Drummond et al. 1982; Edgerton et al. 1979; EPA 1980b; Holler et al. 1989; NIOSH 1984b; Pekari and Aitio 1982; Rick et al. 1982; Siqueina and Fernicola 1981), pentachlorophenol in the urine is a useful biomarker of exposure. In addition, pentachlorophenol can be easily detected and quantified in blood serum at concentrations as low as <1 ppb (Bevenue et al. 1968; EPA 1980b; Needham et al. 1981; NIOSH 1984b) and adipose tissue (Kuehl and Dougherty 1980; Needham et al. 1981; Ohe 1979; Shafik 1973). It has been demonstrated that pentachlorophenol is present in human adipose tissue as an ester of palmitic acid (Ansari et al. 1985). The detection limit for pentachlorophenol in adipose tissue is approximately 5 ppb (Kuehl and Dougherty 1980; Ohe 1979; Shafik 1973). However, measuring pentachlorophenol in body fluids and tissues is not a specific biomarker for pentachlorophenol exposure because other compounds to which exposure may occur (e.g., hexachlorobenzene and lindane) may be metabolized to pentachlorophenol in the body. In addition, the available data do not permit the establishment of a quantitative relationship between levels of pentachlorophenol in the environment and levels in human fluids or tissues. However, it has been reported that repeated workday exposure to pentachlorophenol at a concentration of 0.5 mg/m? has resulted in a maximum steady state level of pentachlorophenol in plasma of about 0.5 mg/L (Wood et al. 1983). Based on samples taken prior to 1989, background levels of up to 0.1 ppm pentachlorophenol could be found in blood and urine of members of the general population who had no recognized exposure to pentachlorophenol (Cranmer and Freal 1970; EPA 1989b; Hill et al. 1989; Kutz et al. 1978). TCHQ, a major urinary metabolite of pentachlorophenol, has potential use as an indicator of exposure to pentachlorophenol. It has been demonstrated that pentachlorophenol is converted to TCHQ by human microsomal enzymes (Juhl et al. 1985). In human and animal studies, TCHQ has been identified as the major urinary metabolite of pentachlorophenol (Ahlborg et al. 1974; Braun et al. 1977; Reigner et al. 1991; Renner 1989). PENTACHLOROPHENOL 89 2. HEALTH EFFECTS 2.5.2 Biomarkers Used to Characterize Effects Caused by Pentachlorophenol The major target organs for both humans and animals exposed to pentachlorophenol are liver and kidney. Clinical manifestations of hepatic and renal toxicity include elevated serum SGOT and SGPT levels in the liver (Armstrong et al. 1969; Bergner et al. 1965; Gordon 1956; Gray et al. 1985; Klemmer 1972; Robson et al. 1969) and increased enzyme levels, increased blood urea nitrogen, and loss of proximal tubular alkaline phosphatase activity in the kidney (Greichus et al. 1979; Kimbrough and Linder 1978; Nishimura et al. 1980). Indices of changes in hepatic oxidative phosphorylation may also be useful as biomarkers for pentachlorophenol-induced liver changes (Ellinger et al. 1991). These effects are not specific for exposure to pentachlorophenol and have been associated with exposure to other compounds such as some chlorinated hydrocarbons. Therefore, the major use of these biomarkers is restricted to comparisons between work groups exposed to the chemical in the workplace and control subjects. Other data indicate that contaminants in the commercial grade product may play an important role in these observed hepatotoxic effects. Human case reports of pentachlorophenol exposure suggest that the central nervous system appears to be a target of pentachlorophenol exposure (Chapman and Robson 1965; Gray et al. 1985; Haley 1977; Robson et al. 1969). As discussed in Section 2.2.2.4, the neurologic syndrome observed following exposure to pentachlorophenol is most likely the direct result of hyperthermia generated by uncoupling of mitochondrial oxidative phosphorylation and not a direct effect on the nervous system. The neurological syndrome observed following exposure to pentachlorophenol can be manifested by lethargy, tachypnea, tachycardia, intermittent delirium, convulsions, cerebral edema, focal swelling of the myelin sheath, and respiratory distress (Chapman and Robson 1965; Gray et al. 1985). However, these symptoms are not specific for pentachlorophenol exposure. In general, there is no simple relationship between nonfatal health effects and levels of penta- chlorophenol detected in serum and urine. Serum levels of pentachlorophenol ranging from 23 to 162 mg/L (ppm) have been reported in cases of fatal overexposure to pentachlorophenol. Serum levels of pentachlorophenol below 1.3 mg/L have not been associated with any adverse health effects (Cline et al. 1989; Klemmer et al. 1980). PENTACHLOROPHENOL 90 2. HEALTH EFFECTS 2.6 INTERACTIONS WITH OTHER CHEMICALS No studies were located regarding the direct toxic interactions of pentachlorophenol with other chemicals in humans or animals. Many studies that compared the toxicity of technical grade versus purified pentachlorophenol have been performed, and all conclude that both the penta- chlorophenol component and the various contaminants contribute to the toxic effects observed. No interactions between these contaminants and the pure pentachlorophenol component of technical grade pentachlorophenol have been demonstrated in some tests of immunotoxicity (Kerkvliet et al. 1985a). However, chlorinated dibenzo-p-dioxins and dibenzofurans are powerful inducers of hepatic microsomal enzymes, many of which are involved in biotransformation and detoxication of pentachlorophenol. Therefore, some of the toxic effects of pure pentachloro- phenol (such as renal effects) may actually be mitigated by chlorinated dibenzo-p-dioxin and dibenzofuran contaminants. Pentachlorophenol may alter the toxicities of other compounds through its inductive action on microsomal metabolic enzymes (Vizethum and Goetz 1979). While this inductive effect has not specifically been demonstrated to alter the toxicity of other compounds, these types of alterations in enzyme activity may influence metabolism and toxicity of many compounds. Pentachlorophenol inhibits cytosolic sulfotransferases (Mulder and Scholtens 1977). Compounds such as n-hydroxy-2- acetylaminofluorene, which are activated by the formation of a sulfate ester, are considerably less toxic in animals pretreated with pentachlorophenol (Meerman et al. 1980). Since pentachlorophenol is metabolized to a small extent by hepatic microsomal enzymes, chemicals that alter the activity of these enzymes can modify metabolism, and subsequently, the toxicity of pentachlorophenol (see discussion above). For example, phenobarbital, a microsomal enzyme inducer, increases biotransformation of pentachlorophenol to TCHQ thereby reducing the level of pentachlorophenol in the body (Ahlborg et al. 1978). A great deal of pentachlorophenol is bound to plasma proteins. Other agents that also have a high affinity for protein bonds (e.g., anticoagulants such as warfarin) can compete with and displace pentachlorophenol from proteins. This action results in a higher level of free circulating pentachlorophenol that can be metabolized, excreted, and/or induce toxic effects. PENTACHLOROPHENOL 91 2. HEALTH EFFECTS Various agents have been used in experimental animals to try to decrease the toxicity of penta- chlorophenol. Cholestyramine is known to bind phenols (Reiman and Walton 1970) and to enhance fecal elimination of chlordecone (Kepone) in rats and humans (Boylan et al. 1977). Rozman et al. (1982) found that cholestyramine enhances excretion of pentachlorophenol in rhesus monkeys and recommends that its use be considered in cases of human pentachlorophenol overexposure. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to pentachlorophenol than will most persons exposed to the same level of pentachlorophenol in the environment. Reasons include genetic make-up, developmental stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These parameters result in decreased function of the detoxication and excretory processes (mainly hepatic, renal, and respiratory) or the pre- existing compromised function of target organs (including effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, Populations With Potentially High Exposure. Groups possibly at greater-than-average risk of suffering from the toxic effects of pentachloro- phenol include persons laboring in hot environments, persons with an inability or decreased ability to disperse body heat, geriatric and pediatric subpopulations, pregnant women, and those that are malnourished or consume an unbalanced diet. People with impaired liver and kidney function are likely to be susceptible to the toxic effects of any chemical/product that is metabolized and/or excreted by these organs, and therefore, may be unusually susceptible to the toxic effects of pentachlorophenol. There is evidence that children are more susceptible to the toxic effects of pentachlorophenol than adults (Chapman and Robson 1965) and that infants are even more susceptible than children, especially by the dermal route of exposure (Armstrong et al. 1969; Barthel et al. 1969; Smith et al. 1967). PENTACHLOROPHENOL 92 2. HEALTH EFFECTS Persons laboring in hot environments are unusually susceptible to the acute toxic effects of pentachlorophenol. The principal effect of pentachlorophenol is hyperthermia induced by the uncoupling of oxidative phosphorylation. The manifestations of overexposure to pentachlorophenol, particularly in persons laboring in a hot environment, are usually those associated with hyperthermia: flushing, intense thirst, sweating, weakness and occasionally, muscle spasms. Persons working in hot environments are unable to disperse excess body heat, resulting in potentially life-threatening hyperthermia. For example, occupational deaths reported by Gray et al. (1985), Bergner et al. (1965), and Menon (1958) were all due to hyperthermia, and the symptoms of hyperthermia described above were exhibited by affected workers prior to death. Many preparations of pentachlorophenol are contaminated with other toxic compounds, and the type and purity of pentachlorophenol used should be kept in mind when reviewing animal studies. Of five gavage studies examining reproductive and/or developmental toxicity of pentachlorophenol in animals (Courtney et al. 1976; Larsen 1976; Larsen et al. 1975; Schwetz et al. 1974) and three dietary studies (Exon and Koller 1982; Schwetz et al. 1978; Welsh et al. 1987), all indicated that pentachlorophenol was not teratogenic in experimental animals but may be embryotoxic and fetotoxic. In the study by Schwetz et al. (1974), fetotoxicity occurred below the dose producing significant maternal toxicity. Individuals with kidney or liver disease may be unusually susceptible to the toxic effects of pentachlorophenol. In certain fatal human cases, the victim was found to have renal insufficiency (Hayes 1982). Experiments have shown that rabbits made nephrotic experimentally were much more susceptible to the toxic effects of pentachlorophenol than were normal rabbits (Hayes 1982). Individuals exposed to other chemicals that bind to plasma proteins (e.g., anticoagulants such as warfarin) may be at greater risk of suffering from pentachlorophenol-induced toxicity as well. 2.8 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to pentachlorophenol. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of PENTACHLOROPHENOL 93 2. HEALTH EFFECTS exposures to pentachlorophenol. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 2.8.1 Reducing Peak Absorption Following Exposure Means of limiting absorption of phenols include washing exposed skin and eyes and removing contaminated clothing in the case of dermal exposure, and inducing emesis, performing gastric lavage, and administering activated charcoal and a cathartic in the case of oral exposure (EPA 1989b). Emesis is induced only if the patient is fully alert and the pentachlorophenol has not been ingested in a solvent so that there is no chance that the stomach contents may be aspirated. If the patient is unconscious or vomiting cannot be induced, intubation, aspiration, and lavage of the stomach are suggested (EPA 1989b). 2.8.2 Reducing Body Burden Various agents have been used in experimental animals to try to decrease the toxicity of pentachlorophenol by reducing body burden. Cholestyramine is known to bind phenols (Reiman and Walton 1970) and to enhance fecal elimination of chlordecone (Kepone) in rats and man (Boylan et al. 1977). In studies performed on rhesus monkeys, oral administration of cholestyramine enhances fecal excretion of pentachlorophenol by interrupting enterohepatic circulation of pentachlorophenol and/or its metabolites (Ballhorn et al. 1981; Rozman et al. 1982). Thus cholestyramine administration may be an effective means of reducing the body burden of pentachlorophenol in humans (Goodman et al. 1990). Hemodialysis and forced diuresis may not be effective means of reducing body burden of phenolic substances, and hemoperfusion has not been sufficiently tested as a means of accelerating elimination of phenols (EPA 1989b). 2.8.3 Interfering with the Mechanism of Action for Toxic Effects Pentachlorophenol exerts its toxic effects by uncoupling mitochondrial oxidative phosphorylation, thereby causing accelerated aerobic metabolism and increased heat production. Physical methods for reducing hyperthermia include cold fluids by mouth if the patient can swallow and cool baths or application of towels dipped in cool water. In addition, to reduce heat production, agitation and involuntary motor activity can be controlled with sedatives such as diazepam or other PENTACHLOROPHENOL 94 2. HEALTH EFFECTS benzodiazepine; however, the use of these drugs in pentachlorophenol overexposure has not been reported. Atropine and salicylates such as aspirin are likely to enhance the toxicity of phenolic substances and should not be administered to control hyperthermia (EPA 1989b). The effect of other antipyretics has not been tested. Since pure pentachlorophenol is metabolized to a small extent by hepatic microsomal enzymes, chemicals that alter activity of these enzymes can modify metabolism, and subsequently, the toxicity of pentachlorophenol. For example, phenobarbital, a microsomal enzyme inducer, increases biotransformation of pentachlorophenol to TCHQ thereby reducing the level of pentachlorophenol in the body (Ahlborg et al. 1978). 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of pentachlorophenol is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of pentachlorophenol. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Existing Information on Health Effects of Pentachlorophenol The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to pentachlorophenol are summarized in Figure 2-3. The purpose of this figure is to illustrate the existing information concerning the health effects of pentachlorophenol. Each dot PENTACHLOROPHENOL 95 2. HEALTH EFFECTS in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs." A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. Most of the literature reviewed concerning the health effects of pentachlorophenol in humans described case reports of individuals exposed either occupationally or in the home following misuse of pentachlorophenol-containing solutions. The predominant route of exposure in such cases is believed to be dermal, but the possibility of some degree of inhalation exposure cannot be ruled out. Therefore, Figure 2-3 reflects that information exists for both inhalation and dermal routes of exposure. One case study was found in the available literature on effects of ingestion of pentachlorophenol by humans. However, all of these reports are limited because of the possibility of concurrent exposure to other potentially toxic substances, present as either contaminants in technical grade pentachlorophenol (i.e., chlorinated dibenzo-p-dioxins and dibenzofurans), as other components in pentachlorophenol-containing mixtures (i.e., pesticides and herbicides), or simply other compounds also in the environment. Additionally, duration and level of exposure to pentachlorophenol generally cannot be quantified from information presented in these anecdotal reports. The database for health effects of pentachlorophenol following ingestion in experimental animals is substantial. However, as can be seen in Figure 2-3, very little information is available on the effects of inhalation and dermal exposure to pentachlorophenol in animals. Furthermore, the health effects associated with acute and intermediate exposure durations are more fully characterized than those associated with chronic exposure. Cytogenetic data on pentachloro- phenol are available almost entirely from in vitro studies. Finally, when evaluating much of the data on health effects of pentachlorophenol, the toxicity of its impurities (which may themselves present a hazard at disposal sites) must be taken into account. The fact remains, however, that pure pentachlorophenol can be toxic and has been shown to be oncogenic in certain species of experimental animals. 96 PENTACHLOROPHENOL 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of Pentachlorophenol SYSTEMIC 5 7 &/ fo ( (3 5 Inhalation ® oO @ oO Oral oOo Dermal ® © oO oO HUMAN SYSTEMIC 7 @ I & &, & & 2% (5 & Inhalation | @ Oral ® 0 06000 © @ Dermal oO ® ANIMAL @ Existing Studies PENTACHLOROPHENOL 97 2. HEALTH EFFECTS 2.9.2 Identification of Data Needs Acute-Duration Exposure. Information is available on effects of acute-duration exposures in humans and experimental animals (rats and mice). The type of information available in humans includes information regarding skin/eye irritation (Baader and Bauer 1951) and acute toxicity (liver, immune system) (Armstrong et al. 1969; Chapman and Robson 1965; Gordon 1956; Hassan et al. 1985; Hoben et al. 1976b; Robson et al. 1969). The type of information available in animals includes LDss (animal) (Borzelleca et al. 1985; Deichmann et al. 1942; Renner et al. 1986; St. Omer and Gadusek 1987), skin/eye irritation (Deichmann et al. 1942), and acute toxicity (liver, immune system) (Kerkvliet et al. 1985a). Thus, while the health effects of acute-duration exposure to technical grade pentachlorophenol are well characterized in humans (hyperthermia and associated effects, hepatotoxicity, dermal and ocular irritation) and are generally the result of impurities present in technical grade and/or uncoupling of oxidative phosphorylation, the concentrations at which such effects occur in humans are usually not known. Therefore, an acute inhalation MRL was not developed because exposure concentrations that cause toxic effects in humans discussed above are not quantified and there are no data on acute inhalation toxicity (other than death) of pentachlorophenol in animals. An acute oral MRL was developed based on a LOAEL identified for adverse developmental effects in rats (Schwetz et al. 1974). Information on concentrations at which both pure and technical grade pentachlorophenol induce adverse effects following acute-duration oral exposure in animals would be useful to identify populations at risk following short-term releases of pentachlorophenol. Although there are no quantitative animal data on pentachlorophenol following acute inhalation exposure, available pharmacokinetic information in animals suggests that absorption is complete and distribution and elimination are similar for oral and inhalation exposure. Therefore, toxicity studies conducted by any route of exposure would be helpful because any results obtained should be qualitatively similar across all routes of exposure, even though concentrations at which effects occur may not be possible to predict. This information is important because populations surrounding hazardous waste sites contaminated with pentachlorophenol may be exposed to this substance via all routes of exposure for brief periods. Intermediate-Duration Exposure. Information is available on effects of intermediate-duration exposures in both humans and experimental animals (rats, mice, and pigs). Exact duration and exposure concentration in human studies generally cannot be quantified because information is PENTACHLOROPHENOL 98 2. HEALTH EFFECTS derived from anecdotal case reports rather than controlled epidemiological studies that describe primarily hepatotoxicity and hematotoxicity (Gordon 1956; Gray et al. 1985; Roberts 1963, 1981; Seghal and Ghorpade 1983). Animal studies described predominantly neurological, hepatic, renal, and immunological endpoints (Greichus et al. 1979; Johnson et al. 1973; Kerkvliet et al. 1982, 1985a, 1985b; Kimbrough and Linder 1978; Knudsen et al. 1974; Nishimura et al. 1980; Savolainen and Pekari 1979). An intermediate inhalation MRL was not calculated because exposure levels that cause toxic effects in humans discussed above are not quantified, and there are no data on intermediate inhalation toxicity of pentachlorophenol in animals. An intermediate oral MRL of 0.001 mg/kg/day was calculated based on hepatotoxicity observed in rats administered technical grade pentachlorophenol in feed for 12 weeks (Knudsen et al. 1974). Little or no information on respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, or dermal/ocular effects in animals (particularly following inhalation exposure), except from older studies using technical grade (contaminated) pentachlorophenol, is available. This information, using both purified and technical grade pentachlorophenol, would be useful to establish which toxic effects are due to pentachlorophenol and which are due to contaminants present in technical grade, and to establish threshold levels in order to identify populations at risk following intermediate-duration releases of pentachlorophenol. Although there are no quantitative animal data on pentachlorophenol following intermediate-duration inhalation exposure, available pharmacokinetic information in animals suggests that absorption is complete and distribution and elimination are similar for oral and inhalation exposure. Therefore, toxicity studies conducted by any route of exposure would be helpful because any results obtained should be qualitatively similar across all routes of exposure, even though concentrations at which effects occur may not be possible to predict. This information is important because populations surrounding hazardous waste sites contaminated with pentachlorophenol may be exposed to this substance for intermediate durations. Chronic-Duration Exposure and Cancer. Few controlled epidemiological studies have been conducted in humans that are not confounded by concurrent exposure to contaminants in technical grade pentachlorophenol or other substances (Fingerhut et al. 1984; Gilbert et al. 1990); Gray ct al. 1985; Greene et al. 1978; Menon 1958; Robinson et al. 1985). However, effects identified in humans following chronic exposure to technical grade pentachlorophenol (most likely by several concurrent routes of exposure) include hepatotoxicity and hematotoxicity. One adequate (NTP 1989) and several inadequate chronic oral toxicity bioassays have been conducted PENTACHLOROPHENOL 99 2. HEALTH EFFECTS in rats and mice (BRL 1968; Schwetz et al. 1978). The effects seen in these studies are predominantly hepatic, renal, and neurological. A chronic inhalation MRL was not developed because exposure concentrations that cause toxic effects in humans are not quantified, and there are no data on chronic inhalation toxicity of pentachlorophenol in animals. A chronic oral MRL was not calculated because the only data available on noncarcinogenic effects of pentachlorophenol in animals are from studies using technical grade pentachlorophenol that identified a LOAEL higher than that used to calculate the intermediate oral MRL. More information on effects (and concentrations at which these effects occur) of chronic exposure of pentachlorophenol in both humans and animals would be useful because human exposures are often long-term and because the probability of exposure is high since pentachlorophenol is quite ubiquitous. Although there are no quantitative animal data on pentachlorophenol following chronic inhalation exposure, available pharmacokinetic information in animals suggests that absorption is complete and distribution and elimination are similar for oral and inhalation exposure. Therefore, toxicity studies conducted by any route of exposure would be helpful because any results obtained should be qualitatively similar across all routes of exposure, even though the levels at which effects occur may not be possible to predict. This information is important because populations surrounding hazardous waste sites contaminated with pentachlorophenol may be exposed to this substance for long periods of time. Epidemiological studies available are inadequate to assess carcinogenic potential of pentachlorophenol in humans (Fingerhut et al. 1984; Gilbert et al. 1990; Gray et al. 1985; Greene et al. 1978; Jappinen et al. 1989; Roberts 1983; Robinson et al. 1985). One adequate (NTP 1989) and several inadequate chronic oral carcinogenicity bioassays have been conducted in animals (BRL 1968; Schwetz et al. 1978). Sufficient evidence for a carcinogenic effect was obtained in the NTP (1989) study, in which a statistically significant increase in incidences of hemangiosarcomas, liver adenomas and carcinomas, and adrenal gland pheochromocytomas was observed in B6C3F, mice administered pentachlorophenol in the feed. No information is available on the carcinogenic potential of pentachlorophenol following inhalation or dermal exposure in animals. Chronic inhalation and dermal bioassays would be useful to determine whether pentachlorophenol induces cancer of the respiratory tract and skin, respectively. Genotoxicity. Only two studies are available on genotoxic effects of pentachlorophenol in humans; both of these are inadequate because of the small number of subjects studied PENTACHLOROPHENOL 100 2. HEALTH EFFECTS (Bauchinger et al. 1982; Wyllie et al. 1982). With the exception of one in vivo study (Fahrig et al. 1978), all information on genotoxic effects of pentachlorophenol in non-humans comes from in vitro studies (predominantly microbial assays), and most yielded negative results (Andersen et al. 1972; Fahrig 1974; Fahrig et al. 1978; Lemma and Ames 1975; Moriya et al. 1983; Waters et al. 1982). In contrast, the metabolite TCHQ caused gene mutations and induction of micronuclei in Chinese hamster V-79 cells (Jansson and Jansson 1991, 1992) and DNA damage in Chinese hamster ovary cells (Ehrlich 1990). Although these findings tend to suggest that this metabolite, rather than the parent, may be the genotoxic agent, results have not been confirmed and available information is too limited to support this assessment. Similarly, no conclusions can be drawn from genetic toxicology studies conducted with pentachlorophenol. Since the majority of in vitro testing with pentachlorophenol was conducted without auxiliary metabolic activation, it is conceivable that under appropriate conditions, genotoxic potential of pentachlorophenol would be uncovered. Evidence that pentachlorophenol requires metabolic conversion to a reactive state is supported by a weak, but positive, mutagenic response observed in the in vivo mouse spot test (Fahrig et al. 1978). Before definitive conclusions can be reached, the parent and primary metabolites should be subjected to a full battery of in vitro and in vivo studies that includes all major genetic end points. Reproductive Toxicity. Except for one brief report that provided evidence that prolonged exposure to wood preservatives containing pentachlorophenol was associated with adverse reproductive effects in women (Gerhard et al. 1991), no information on reproductive effects of pentachlorophenol in humans is available. Furthermore, no standard reproduction studies in experimental animals were located in the literature. However, decreases in litter size and a high incidence of resorptions were reported in rats orally administered 25-30 mg/kg/day of pentachlorophenol in nonstandard reproductive toxicity studies (Exon and Koller 1982; Schwetz et al. 1974, 1978; Welsh et al. 1987). Given the high potential for human exposure to pentachloro- phenol, more information on potential reproductive toxicity of this compound would be useful. To this end, any oral and/or inhalation subchronic studies that are conducted should include examination of reproductive organ pathology. Available pharmacokinetic information in animals suggests that absorption is complete and distribution and elimination are similar for oral and inhalation exposure. Therefore, toxicity studies conducted by any route of exposure would be helpful because results obtained should be qualitatively similar to what would be expected by PENTACHLOROPHENOL 101 2. HEALTH EFFECTS other routes of exposure, even though concentrations at which effects occur may not be possible to predict. Developmental Toxicity. Information on developmental effects of pentachlorophenol in humans resulting from ingestion was not found. Data in rats indicate that pentachlorophenol is not teratogenic but is embryo- and fetotoxic following oral exposure (Larsen et al. 1975). In the teratogenicity study of Schwetz et al. (1974), the highest dose level of purified pentachlorophenol (5 mg/kg/day, which was below the maternally toxic level) delayed ossification of skull bones in rats tested. Thus, there is no available standard teratogenicity study that shows a NOAEL for pentachlorophenol-induced fetotoxicity. This information would be useful in order to predict threshold concentrations for adverse developmental effects associated with exposure to pentachlorophenol. The available pharmacokinetic information in animals suggests that absorption is complete and distribution and elimination are similar for oral and inhalation exposure. Therefore, toxicity studies conducted by any route of exposure would be helpful because results obtained should be qualitatively similar to what would be expected by other routes of exposure, even though the concentrations at which effects occur may not be possible to predict. Immunotoxicity. One brief report offered evidence that prolonged exposure to wood preservatives containing pentachlorophenol was associated with adverse reproductive effects in women that were secondary to endocrine or immunological disorders (Gerhard et al. 1991). Some information is also available on immunotoxic effects of pentachlorophenol in humans resulting from occupational exposure. Two skin diseases, pemphigus vulgaris and chronic urticaria, have an immunologic etiology and have been associated with pentachlorophenol exposure in humans (Lambert et al. 1986). The available data in mice indicate that technical grade pentachlorophenol affects a wide range of immune functions, such as humoral and cellular immunity, susceptibility to tumor induction, and complement activity (Holsapple et al. 1987; Kerkvliet et al. 1982, 1985a, 1985b; White and Anderson 1985). Many of the effects reported may be due to impurities present in technical grade pentachlorophenol. However, tests of cell-mediated and humoral immune function conducted with normal human lymphocytes in vitro using both technical and pure pentachlorophenol indicate that pure compound is directly immunotoxic to these cells, affecting both T-cell responses and humoral immune reactivity (Lang and Mueller-Ruchholtz 1991). Tests for immune competence in humans have not been conducted in cases of penta- chlorophenol intoxication. It is difficult to extrapolate immune function parameters measured in PENTACHLOROPHENOL 102 2. HEALTH EFFECTS animals to humans. Thus, the relevance of these immune responses observed in animals to what may occur in humans following long-term low-level exposure to pentachlorophenol is not known. Therefore, more information from controlled human studies in which immunologic function is studied would be useful. Neurotoxicity. The available information suggests that neurological effects occur in humans following short-term high-level exposure to pentachlorophenol (Chapman and Robson 1965; Gray et al. 1985; Haley 1977; Robson et al. 1969). These effects are most likely secondary to a generalized uncoupling of oxidative phosphorylation leading to hyperthermia. Very little information is available on long-term neurotoxic effects of low-level exposure to pentachlorophenol in humans or animals. However, chronic exposure to pentachlorophenol vapors at a chemical plant resulted in no detectable neurophysiological effects in exposed workers (Triebig et al. 1987). Additional long-term neurotoxicity studies in animals, using sensitive functional and neuropathological tests, would be helpful in determining if pentachlorophenol is neurotoxic following chronic exposure, but there is currently no strong indication that the nervous system is a target for pentachlorophenol-induced toxicity following long-term low-level exposure. Epidemiological and Human Dosimetry Studies. Most available information on effects of pentachlorophenol in humans comes from cases of acute exposure following home use of penta- chlorophenol-containing wood preservatives and herbicides, and occupational exposures in agricultural and wood-treatment industries (Baader and Bauer 1951; Begley et al. 1977; Chapman and Robson 1965; Gordon 1956; Hassan et al. 1985; Menon 1958; Roberts 1963, 1983, 1990: Robson et al. 1969). Limitations inherent in these studies include unquantified exposure concentrations and durations, as well as concomitant exposure to chlorophenol mixtures and contaminants. The few available industrial surveys and epidemiological studies are limited in their usefulness because of small sample size, short follow-up periods, and brief exposure periods. Despite their inadequacies, acute exposure studies in humans suggest that pentachlorophenol can adversely affect the liver, kidney, skin, blood, lungs, and central nervous system. One long-term study of workers in Hawaii did not demonstrate any long-term toxic or carcinogenic effects of pentachlorophenol in exposed workers (Gilbert et al. 1990). Well-controlled epidemiological studies of people living in close proximity to areas where pentachlorophenol has been detected in surface and groundwater, near industries releasing pentachlorophenol, near hazardous waste sites, PENTACHLOROPHENOL 103 2. HEALTH EFFECTS and of people occupationally exposed could add to and clarify the existing database on penta- chlorophenol-induced human health effects. Biomarkers of Exposure and Effect Exposure. Since pentachlorophenol is excreted in urine largely unchanged (Ahlborg et al. 1974; Braun et al. 1979; Larsen et al. 1972; Reigner et al. 1991) and since it can be easily detected in the urine (Chou and Bailey 1986; Drummond et al. 1982; Edgerton et al. 1979; EPA 1980b; Holler et al. 1989; NIOSH 1984b; Pekari and Aitio 1982; Rick et al. 1982; Siqueina and Fernicola 1981), the presence of pentachlorophenol in urine may be used as a biomarker of exposure to pentachlorophenol. TCHQ, a urinary metabolite of pentachlorophenol (Ahlborg et al. 1974; Braun et al. 1977; Reigner et al. 1991; Renner 1989), may possibly be used as a biomarker of exposure to pentachlorophenol if reliable methods of detection are developed. In general, no attempts have been made to correlate levels of pentachlorophenol in the body with levels absorbed through skin or via inhalation. However, data from a study in log homes demonstrate a positive correlation between serum and urine levels of pentachlorophenol and indoor air levels of this compound (Hosenfeld et al. 1986). At this time, the only known biomarker is the presence in urine of the parent compound, pentachlorophenol, and possibly its metabolite, TCHQ; it would be useful to develop alternative biomarkers to complement this analysis. Effect. Potential biomarkers of effect for short-term exposure to pentachlorophenol include lethargy, tachypnea, tachycardia, intermittent delirium, convulsions, cerebral edema, focal swelling of the myelin sheath, and respiratory distress (Chapman and Robson 1965; Gray et al. 1985). These effects are not specific for pentachlorophenol exposure. Biomarkers of effect for intermediate- and long-term exposure to pentachlorophenol include elevated serum SGOT and SGPT levels in the liver (Armstrong et al. 1969; Bergner et al. 1965; Gordon 1956; Gray et al. 1985; Klemmer 1972; Robson et al. 1969) and increased enzyme levels, increased blood urea nitrogen, and loss of proximal tubular alkaline phosphatase activity in the kidney (Greichus et al. 1979; Nishimura et al. 1980; Kimbrough and Linder 1978). However, these also are not specific for pentachlorophenol. These biomarkers are only indicative of effect and are not useful for dosimetry. Development of additional, more sensitive biomarkers that are specific for pentachlorophenol effects would be useful in monitoring populations at high risk. PENTACHLOROPHENOL 104 2. HEALTH EFFECTS Adequate methods exist for analysis of pentachlorophenol in human body tissues and fluids. However, with the possible exception of skin disease and renal toxicity, no good quantitative correlation can be drawn between body levels of pentachlorophenol and adverse health effects based on available data. If epidemiological studies are conducted that correlate pentachloro- phenol exposure with specific adverse health effects (such as kidney or liver dysfunction), then it may be possible to correlate quantitatively these effects with changes in tissue and/or body fluid levels of pentachlorophenol. Absorption, Distribution, Metabolism, and Excretion. The database for inhalation and dermal absorption of pentachlorophenol in humans consists primarily of qualitative evidence from occupational case studies (Casarett et al. 1969; Cline et al. 1989; Hosenfeld et al. 1986; Jones et al. 1986). Limited quantitative information is available on ingestion of pentachlorophenol in humans (Braun et al. 1979; Uhl et al. 1986). More quantitative reliable absorption data for all routes in humans would be useful to better predict the potential for toxic responses to penta- chlorophenol in humans exposed under various conditions. Available data indicate that pentachlorophenol is rapidly and completely absorbed following oral absorption in both humans and animals. The database is sufficient for oral route of intake in animals (Ahlborg et al. 1974; Braun and Sauerhoff 1976; Braun et al. 1977; Meerman et al. 1983; Reigner et al. 1991) but is lacking for inhalation and dermal absorption (Hoben et al. 1976¢). Because of the lack of human absorption data for these two routes of exposure, more data in animals would be useful in order to predict the rate and extent of inhalation and dermal absorption of pentachlorophenol in humans. The only information that exists regarding distribution of pentachlorophenol in humans comes from autopsy reports where concentration, duration, and route of pentachlorophenol exposure are not known (Grimm et al. 1981). Pentachlorophenol distribution is well characterized in animals following oral and intraperitoneal exposure (Braun and Sauerhoff 1976; Braun et al. 1977) but not following inhalation or dermal exposure. The oral distribution data can be used to predict pentachlorophenol distribution in humans. More animal data on pentachlorophenol distribution following inhalation and dermal exposure would be useful in terms of predicting its distribution in humans following exposure by these routes. PENTACHLOROPHENOL 105 2. HEALTH EFFECTS There are adequate data to assess the metabolic fate of pentachlorophenol in humans and animals (Ahlborg et al. 1974; Braun and Sauerhoff 1976; Braun et al. 1977, 1979; Renner 1989; Renner and Hopfer 1990; Uhl et al. 1986). Additional studies may shed light on why biotransformation varies across species and how protein binding affects the rate of metabolism. Knowledge of the potential effect of route of administration on metabolism would be useful. The kinetics of pentachlorophenol excretion are well characterized in animals, and data do exist for humans (Ahlborg et al. 1974; Braun and Sauerhoff 1976; Braun et al. 1977, 1979; Larsen et al. 1972; Reigner et al. 1991). Further study into (1) the underlying basis for species and sex differences observed; (2) the disposition of pentachlorophenol during long-term low-level exposure in humans and animals; and (3) the potential for pentachlorophenol to accumulate in humans would be useful in devising methods for reducing absorption and body burden in humans exposed to pentachlorophenol. Comparative Toxicokinetics. The database is sufficient with regard to comparative toxicokinetics of pentachlorophenol in several species of experimental animals and humans (Ahlborg et al. 1974; Braun and Sauerhoff 1976; Braun et al. 1977, 1979; Meerman et al. 1983; Reigner et al. 1991; Renner 1989; Renner and Hopfer 1990; Uhl et al. 1986). Methods for Reducing Toxic Effects. Pentachlorophenol can be absorbed through inhalation, oral, or dermal routes. Methods are available for reducing absorption following oral and dermal exposure to pentachlorophenol; however, since gastrointestinal absorption of pentachlorophenol in humans is rapid (Braun et al. 1979), these methods (washing skin and eyes, emesis, lavage, activated charcoal, and catharsis) (EPA 1989b) are useful only immediately following exposure to the chemical. Based on animal studies, cholestyramine administration is recommended in cases of human pentachlorophenol overexposure to enhance elimination of pentachlorophenol (Goodman et al. 1990); however, its use in humans has not been sufficiently tested. Also, hemoperfusion (as a means of enhancing pentachlorophenol elimination) and administration of sedatives or antipyretics (as a means of reducing heat production) have not been adequately tested in cases of pentachlorophenol overexposure. Data on cholestyramine administration, hemoperfusion, and administration of sedatives or antipyretics as treatment methods would be useful. In addition, with the exception of physical means to reduce body temperature in individuals that become PENTACHLOROPHENOL 106 2. HEALTH EFFECTS hyperthermic, no established methods for mitigation of health effects resulting from pentachlorophenol exposure were located. 2.9.3 On-going Studies Information on all on-going studies cited in this section was obtained from CRISP (1992) and FEDRIP (1992). NIOSH is developing a Dioxin Study Registry, which has a subpopulation of 2,000 workers exposed only to technical pentachlorophenol. Dr. E. Bittar at the University of Wisconsin is currently studying mechanisms by which chlorophenols act as cytotoxins. Single barnacle muscle fibers together with two cell-free model systems (the photoprotein aequorin and firefly) are being used to test the hypothesis that pentachlorophenol acts as a cellular toxin by disturbing production of ATP. Dr. Ghulam Ansari at the University of Texas Medical Branch is studying lipid conjugates of xenobiotics, including pentachlorophenol in rats and mice, in an attempt to establish the contribution of these conjugates to intrinsic toxicity of their parent xenobiotics. Dr. P. Kurtz, under the sponsorship of the National Institute of Environmental Health Services, is characterizing the dose-response relationship and toxicity of pentachlorophenol administered by dosed feed to rats. PENTACHLOROPHENOL 107 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regarding the chemical identity of pentachlorophenol is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of pentachlorophenol is located in Table 3-2. TABLE 3-1 . Chemical Identity of Pentachlorophenol and Sodium Pentachlorophenate® Characteristic Pentachlorophenol Sodium pentachlorophenate Synonym(s) Registered trade name(s) Chemical formula Chemical structure Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS DOT/UN/NA/IMCO shipping HSDB NCI PCP; penchiorol; penta; pentachlorophenate; 2,345 6-pentachlorophenol? Chlon; Dowicide 7; Dowicide EC-7; Dura Treet II; EP 30; Fungifen: Grundier Arbezol; Lauxtol; Liroprem; Penta Concentrate; Penta Ready; Penta WR; Permasan; Santophen 20; Woodtreat CgHClsO 87-86-5 SM6300000 U242; FO27 7216842 NA 2020 894 C54933; C55378; C56655 Pentachlorophenol sodium; pentachlorophenol sodium salt: pentachlorophenoxy sodium: pentaphenate Dow Dormant Fungicide: Dowicide G; Dowicide G-St; Mystox D; Napclor-G; Santobrite; Sapco25 Weedbeads CgClsONa ONa 131-52-2 SM6490000 No data No data UN2567; IMO6.1 761 No data 8All information obtained from HSDB 1992 except where noted. bRTECS 1991 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute: NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/ Technical Assistance Data System; RTECS = Registry of Toxic Effects of (Chemical Substances NOILYWHOSNI TVOISAHd ANV TVOIN3HO ‘€ TONIHJOHOTHOVIN3d 801 TABLE 3-2. Physical and Chemical Properties of Pentachlorophenol and Sodium Pentachlorophenate® Property Pentachlorophenol Sodium pentachlorophenate Molecular weight Color Physical state Melting point Boiling point Density Odor Odor threshold: Water Solubility: Water Organic solvent(s) Partition coefficients: Log Koy Log Koc Vapor pressure Henry's law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits 266.35 Colorless or white (pure): dark gray to brown (crude product) Crystalline solid (pure): pellets or powder (crude product)? 190°C 309-310°C (decomposes) 1.978 g/mL at 22°C/4°C Phenolic: very pungent (only when hot) 0.857 mg/L at 30°C: 12.0 mg/L at 60°C b.€ 14 mg/L at 20°C Very soluble in alcohol and ether; soluble in benzene; slightly soluble in cold petroleum ether 5.01P 45 0.00011 mm Hg’ 34x10" atm-m3/mol9 No data No data No data No data No data 288.34 White or tan Flakes or powder No data No data No data No data No data 330.000 mg/L at 25°C Soluble in acetone and ethanol No data No data No data No data No data No data No data No data No data aAll information obtained from HSDB 1992 unless otherwise noted. erschueren 1983 CHoak 1957 dBudavari et al. 1989 €Schellenberg et al. 1984 f Callahan 1979 9Lyman et al. 1982 NOILVIWHOGNI TYOISAHd ANV TVOINIHO '€ TON3IHdJOHOTHOVLN3d 601 PENTACHLOROPHENOL 111 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.1 PRODUCTION Vulcan Chemicals, a division of Vulcan Materials Company (Wichita, Kansas), is the only current domestic manufacturer of pentachlorophenol (SRI 1991). Pentachlorophenol is produced by the stepwise chlorination of phenols in the presence of catalysts (anhydrous aluminum chloride or ferric chloride). Outside of the United States, it is also produced by the alkaline hydrolysis of hexachlorobenzene. Typically, commercial grade pentachlorophenol is 86% pure. Contaminants generally consist of other polychlorinated phenols, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans. Pentachlorophenol has also been marketed in the past as a water- soluble sodium salt, a 5% emulsifiable concentrate, or a 3-40% solution in formulation with other chlorophenols, methylene bisthiocyanate, or copper naphthenate (IARC 1979). Production volumes for 1983-1986 were as follows: 45 million pounds in 1983; 42 million pounds in 1984; 38 million pounds in 1985; 32 million pounds in 1986 (Mannsville 1987). More recent production data are not available. For further information on facilities in the United States that manufacture or process pentachlorophenol, refer to Table 4-1. Table 4-1 is derived from Toxics Release Inventory (TRI) data and reports only those facilities that release pentachlorophenol. 4.2 IMPORT/EXPORT U.S. consumption of pentachlorophenol for 1986 was reported to be 28 million pounds (CMR 1987). In 1982, 121,000 pounds of pentachlorophenol were imported to the United States (328,000 pounds were imported in 1980). In 1985, 3 million pounds of pentachlorophenol were exported, and in 1986, 2 million pounds were exported (Mannsville 1987). 4.3 USE Pentachlorophenol was one of the most widely used biocides in the United States. It was registered for use by EPA as an insecticide (termiticide), fungicide, herbicide, molluscicide, algicide, disinfectant, and as an ingredient in antifouling paint (Cirelli 1978a), but it is now a restricted-use pesticide (CELDS 1992; EPA 1984). The principal use of pentachlorophenol is as a wood preservative (registered by EPA as such). The treatment of wood for utility poles TABLE 4-1. Facilities that Manufacture or Process Pentachlorophenol® Facility . b Location Range of maximum amounts on site in pounds Activities and uses BALDWIN POLE & PILING CO. INC. STALLWORTH TIMBER CO. T. R. MILLER MILL CO. INC. CAHABA PRESSURE TREATED FORESTPRODUCTS INC. HUXFORD POLE & TIMBER CO. INC. KOPPERS INDUSTRIES INC. WEYERHAEUSER CO. WOOD TREATING PLANT J. H. BAXTER & CO. SELMA TREATING CO. WILLIAM C. MEREDITH CO. INC. ATLANTIC WOOD INDUSTRIES INC. HAWAII WOOD PRESERVING CO. L. D. MCFARLAND CO. BROWN WOOD PRESERVING CO. INC. MARINE SHALE PROCESSORS INC. COLFAX CREOSOTING CoO. DIS-TRAN PRODUCTS INC. HATHEWAY & PATTERSON CO. INC. BELL LUMBER & POLE CoO. CHAPMAN CHEMICAL CoO. INTERNATIONAL PAPER JOPLIN MO KOPPERS INDUSTRIES INC. NASA JOHN C. STENNIS SPACE CENTER INTERNATIONAL PAPER IDAHO POLE CoO. GENERAL WOOD PRESERVING CO. INC. HUGHES BROTHERS INC. HAWTHORNE ARMY AMMUNITION PLANT CENTRAL FOREST PRODUCTS INC. J. H. BAXTER & CO. L. D. MCFARLAND CO. TAYLOR LUMBER & TREATING INC. WOOD PRESERVING DIV. KOPPERS INDUSTRIES INC. WHEELER LUMBER OPERATIONS LUMBER DIV. CHAPMAN CHEMICAL CO. CONROE CREOSOTING CO. ATLANTIC WOOD INDUSTRIES INC. J.H. BAXTER & CO. BROOKS MFG. CO. BAY MINETTE, AL BEATRICE, AL BREWTON, AL BRIERFIELD, AL HUXFORD, AL MONTGOMERY, AL DE QUEEN, AR LONG BEACH, CA SELMA, CA EAST POINT, GA PORT WENTWORTH, GA KAHULUI, HI SANDPOINT, ID LOUISVILLE, KY AMELIA, LA PINEVILLE, LA PINEVILLE, LA MANSFIELD, MA NEW BRIGHTON, MN CABOOL, MO JOPLIN, MO GRENADA, MS STENNIS SPACE CEN, MS WIGGINS, MS BOZEMAN, MT LELAND, NC SEWARD, NE HAWTHORNE, NV HUGO, OK EUGENE, OR EUGENE, OR SHERIDAN, OR FLORENCE, SC WHITEWOOD, SD MEMPHIS, TN CONROE, TX PORTSMOUTH, VA ARLINGTON, WA BELLINGHAM, WA 10,000-99,999 100,000, 000-499, 999, 999 10,000-99,999 10,000-99,999 10,000-99,999 1,000,000-9, 999,999 100, 000-999, 999 100, 000-999, 999 10,000-99,999 10,000-99,999 10,000-99,999 0-99 10,000-99,999 10,000-99, 999 10,000-99,999 100, 000-999, 999 1,000-9,999 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99, 999 0-99 100,000-999, 999 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 1,000-9,999 100,000-999, 999 10,000-99,999 100,000-999, 999 1,000,000-9, 999,999 1,000-9,999 1,000,000-9,999,999 10,000-99,999 100, 000-999, 999 100, 000-999, 999 10,000-99, 999 As As As As As As As As As As As As As As As As As As As As As As In As As As As In As As As As As As As As As As As an article component an article component an article component an article component an article component an article component an article component an article component a formulation component an article component an article component a formulation component a formulation component an article component a reactant an article component an article component an article component an article component a formulation component an article component an article component ancillary or other uses an article component a formulation component an article component an article component ancillary or other uses a formulation component an article component a formulation component an article component an article component a formulation component a reactant, as a formulation component an article component an article component an article component an article component IVSOdSIA ANY '3SN 'LHOdWI ‘NOILONAOHd 'v TON3IHJOHOTHOVIN3d Zhi TABLE 4-1. Facilities That Manufacture or Process Pentachlorophenol (continued) Facility QESER CO. PACIFIC WOOD TREATING CORP. PACIFIC SOUND RESOURCES CASCADE POLE CO. COWBOY TIMBER TREATING INC. "Derived from TRI91 (1993) post Office state abbreviations used : b Location BELLINGHAM, WA RIDGEFIELD, WA SEATTLE, WA TACOMA, WA MANDERSON, WY Range of maximum amounts on site in pounds 10,000-99,999 10,000-99,999 10,000-99,999 10,000-99,999 1,000-9,999 Activities and uses As an article component As a formulation component, as an article component As an article component As a formulation component As a manufacturing aid I¥SOdSIa ANY ‘3sSn ‘1HOdWI ‘NOILONAOHd ¥ JON3IHdOHOTHOVIN3d eli PENTACHLOROPHENOL 114 4. PRODUCTION, IMPORT, USE, AND DISPOSAL represents 80% of the U.S. consumption of pentachlorophenol (CMR 1987). However, penta- chlorophenol is no longer contained in wood preserving solutions or insecticides and herbicides available for home and garden use since it is a restricted-use pesticide. Pentachlorophenol is used for the formulation of fungicidal and insecticidal solutions and for incorporation into other manufactured pesticide products. These non-wood uses account for no more than 2% of U.S. pentachlorophenol consumption in recent years (Mannsville 1987). This wide spectrum of uses can be partially attributed to the solubilities of the nonpolar pentachlorophenol in organic solvents and the sodium salt in water. 4.4 DISPOSAL After treatment with sodium bicarbonate or a sand-soda ash mixture, pentachlorophenol can be incinerated. Incineration of pentachlorophenol is one of the most important sources of polychlorinated dibenzo-p-dioxins and dibenzofurans, so care must be taken during this process (Karasek and Dickson 1987). Pentachlorophenol has been designated as a hazardous substance, a hazardous pollutant, a toxic pollutant, and a hazardous waste by EPA. Disposal of pentachlorophenol is subject to EPA restrictions (EPA 1991a, 1991b). PENTACHLOROPHENOL 115 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Pentachlorophenol has been one of the most heavily used pesticides in the United States. The compound is found in all environmental media as a result of its past widespread use. In addition, a number of other chemicals, including hexachlorobenzene, pentachlorobenzene, and benzenehexachloride isomers, are known to be metabolized to pentachlorophenol. Current releases of pentachlorophenol to the environment are more limited than historical releases of the compound as a result of changing use patterns (e.g., phase-out of slimicide use in water cooling towers) and waste treatment practices (e.g., closing of on-site evaporation ponds at wood- treatment facilities). Pentachlorophenol is currently regulated as a restricted-use pesticide. Pentachlorophenol is stable to hydrolysis and oxidation, but the compound is rapidly photolyzed by sunlight and can be metabolized by microorganisms, animals, and plants. Adsorption to soils and sediments is more likely to occur under acidic conditions than under neutral or basic conditions. The compound has been found to bioaccumulate to modest levels (e.g., bioconcentration factors of <1,000), but food chain biomagnification has not been observed. In recent decades, pentachlorophenol has been widely detected in human urine, blood, and adipose tissue among members of the general population. Human exposure to pentachlorophenol is believed to occur via inhalation of indoor and workplace air, ingestion of contaminated water and food, and direct dermal contact with pentachlorophenol-treated wood products. Since pentachlorophenol is no longer used in the treatment of wood products used in new residences and agricultural buildings, future indoor air exposure to this compound from these sources is likely to be minimal. Pentachlorophenol has been identified in at least 247 of the 1,350 hazardous waste sites on the NPL (HAZDAT 1993). However, the number of sites evaluated for pentachlorophenol is not known. The frequency of these sites can be seen in Figure 5-1. Of these sites, 246 are located in the United States and 1 is located in the Commonwealth of Puerto Rico (not shown). FIGURE 5—1. FREQUENCY OF NPL SITES WITH PENTACHLOROPHENOL CONTAMINATION * FREQUENCY BEH3FH 1 TO 4 SITES BEd 5s TO 9 SITES #l 10 TO 13 SITES Bl 17 0 21 SITES Derived from HazDat 1993 34NSOdX3 NVWNH "HO4 TVILN3LOd 'S JON3IHJOHOTHOV.LN3d gti PENTACHLOROPHENOL 117 5. POTENTIAL FOR HUMAN EXPOSURE 5.2 RELEASES TO THE ENVIRONMENT Pentachlorophenol is ubiquitously distributed in the environment. It has been detected in surface waters and sediments, rainwater, drinking water, aquatic organisms, soils, and food, as well as human milk, adipose tissue, and urine. The compound has been identified in at least 246 of the 1,350 hazardous waste sites on the NPL (HAZDAT 1993). The majority of estimated historical annual pentachlorophenol releases during production and use are to the atmosphere (about 1.4 million pounds [620 metric tons]) from wood preservation plants and cooling towers, and to land (about 1.9 million pounds [890 metric tons]) from wood preservation and domestic use as a preservative. Pentachlorophenol is also released into the aquatic environment, especially in runoff waters and wood-treatment plant effluents. Based on the available information, discharges to water, both direct and through municipal waste-water treatment facilities, are estimated to be about 26,000 pounds (12 metric tons) and 11,000 pounds (5 metric tons), respectively (EPA 1980f). It should be noted, however, that much of these data, and data discussed in the following sections, were collected before pentachlorophenol became a restricted use pesticide. Current releases may be much more limited, as indicated by the releases reported to the Toxics Release Inventory (TRI). However, total current environmental releases are probably higher than the TRI estimates because only certain types of facilities are required to report; the list of facilities is not exhaustive. 5.2.1 Air Pentachlorophenol is released directly into the atmosphere via volatilization from treated wood products. Evaporation of pentachlorophenol-treated industrial process waters from cooling towers was an additional source of historical atmospheric releases of the compound. Historical atmospheric releases included those from cooling towers, where pentachlorophenol and its sodium salt were used as slimicides in cooling tower waters. However, pentachlorophenol and its salt are no longer commonly used for this purpose (Vulcan 1989). Emissions during production are considered to be relatively insignificant in volume and are geographically restricted to the Vulcan Materials facility in Wichita, Kansas. Physical removal PENTACHLOROPHENOL 118 5. POTENTIAL FOR HUMAN EXPOSURE mechanisms, such as wet deposition, are important processes affecting pentachlorophenol concentrations in the atmosphere. Pentachlorophenol has historically been estimated to volatilize from the surface of pentachloro- phenol-treated wood products at an estimated rate of 760,000 pounds (344 metric tons) annually, or roughly 2% of the total amount of preservative applied. These estimates are representative of usage of the compound in those applications in the 1970s (EPA 1980f). As much as 500,000 pounds annually (228 metric tons) of pentachlorophenol used in cooling tower waters as an anti-fouling agent have been released to the atmosphere through volatilization with heated water and steam in the past (EPA 1980f). However, pentachlorophenol is no longer commonly used for this purpose (Vulcan 1989). According to the TRI, an estimated total of 12,508 pounds of pentachlorophenol, amounting to 77% of the total environmental release, were discharged to the atmosphere from manufacturing and processing facilities in the United States in 1991 (TRI91 1993) (Table 5-1). The data listed in the TRI should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.2.2 Water Pentachlorophenol releases to surface water occur through direct discharge and direct entry from numerous non-point sources, including treated wood. In addition, pentachlorophenol is transported to surface waters from the atmosphere by wet deposition, and from soil by runoff and leaching. Approximately 90% of wood-treatment plants evaporate their waste water and, consequently, have no direct discharge to surface waters. The remainder of the plants discharge to municipal waste-water treatment facilities. Total annual pentachlorophenol releases to municipal waste-water treatment facilities were estimated to be 12,000 pounds (5.3 metric tons) (EPA 1979). About 2 metric tons of pentachlorophenol used as a biocide in cooling tower waters were estimated to have been discharged to surface waters in 1978 (EPA 1979a). In addition, industries such as leather tanning and textile factories may have released up to 4,400 pounds (2 metric tons) TABLE 5-1. Releases to the Enviroment from Facilities that Manufacture or Process Pentachlorophenol® Reported amounts released in pounds off-site . Underground Total POTW waste Facility Location Air injection Water Land environment ® transfer transfer BALDWIN POLE & PILING BAY MINETTE, AL 2 0 0 0 2 0 7 CO. INC. STALLWORTH TIMBER CO. BEATRICE, AL 6,600 0 5 0 6,605 0 0 T. R. MILLER MILL co. BREWTON, AL 250 0 5 0 255 0 1,750 INC. CAHABA PRESSURE TREATED BRIERFIELD, AL 255 0 250 0 505 0 0 FORESTPRODUCTS INC. HUXFORD POLE & TIMBER HUXFORD, AL 3 0 0 0 3 0 1,900 CO. INC. KOPPERS INDUSTRIES INC. MONTGOMERY, AL 46 0 0 0 46 42 540 WEYERHAEUSER CO. WOOD DE QUEEN, AR 2,505 0 530 5 3,040 0 740 TREATING PLANT J. H. BAXTER & CO. LONG BEACH, CA 255 0 0 0 255 0 250 SELMA TREATING CO. SELMA, CA 10 0 0 0 10 0 1,000 WILLIAM C. MEREDITH CO. EAST POINT, GA 255 0 5 250 510 0 10 INC. ATLANTIC WOOD INDUSTRIES PORT WENTWORTH, GA 6 0 0 0 6 0 2,036 INC. HAWAII WOOD PRESERVING KAHULUI, HI 0 0 0 0 0 0 5 co. L. D. MCFARLand CO. SandPOINT, 1D 8 0 5 0 13 0 462 BROWN WOOD PRESERVING LOUISVILLE, KY 255 0 250 0 505 0 2,500 CO. INC. MARINE SHALE PROCESSORS AMELIA, LA 0 0 0 0 0 0 0 INC. COLFAX CREOSOTING CO. PINEVILLE, LA 5 0 0 0 5 13 5 DIS-TRAN PRODUCTS INC. PINEVILLE, LA 0 0 0 0 0 1" 760 HATHEWAY & PATTERSON CO. MANSFIELD, MA 10 0 5 0 15 0 0 INC. BELL LUMBER & POLE CoO. NEW BRIGHTON, MN 53 0 0 0 53 0 0 CHAPMAN CHEMICAL CoO. CABOOL, MO 0 0 0 0 0 0 0 INTERNATIONAL PAPER JOPLIN, MO 15 0 0 0 15 1" 7,047 JOPLIN MO KOPPERS INDUSTRIES INC. GRENADA, MS 34 0 0 0 34 2 8,020 NASA JOHN C. STENNIS STENNIS SPACE, MS 5 0 0 0 5 0 0 SPACE CENTER INTERNATIONAL PAPER WIGGINS, MS 21 0 0 0 21 12 759 IDAHO POLE CO. BOZEMAN, MT 1 0 9 0 10 0 217 GENERAL WOOD PRESERVING LELand, NC 3 0 0 0 3 0 53,420 CO. INC. 3HNSOdX3 NVYANH HOA TVILN3LOd 'S JON3IHJOHOTHOVINId 6h TABLE 5-1. Releases to the Environment from Facilities That Manufacture or Process Pentachlorophenol (continued) Reported amounts released in pounds off-site b Underground Total POTW waste Facility Location Air injection Water Land environment” transfer transfer HUGHES BROTHERS INC. SEWARD, NE 10 0 5 0 15 0 0 HAWTHORNE ARMY HAWTHORNE, NV 0 0 0 750 750 0 0 AMMUNITION PLANT CENTRAL FOREST PRODUCTS HUGO, OK 5 0 0 0 5 0 0 INC. J. H. BAXTER & CO. EUGENE, OR 10 0 250 0 260 0 500 L. D. MCFARLand CO. EUGENE, OR 6 0 14 0 20 0 56 TAYLOR LUMBER & TREATING SHERIDAN, OR 10 0 250 250 510 0 1,250 INC. WOOD PRESERVING DIV. KOPPERS INDUSTRIES INC. FLORENCE, SC 400 0 300 0 700 14 180,076 WHEELER LUMBER WHITEWOOD, SD 0 0 0 0 0 0 0 OPERATIONS LUMBER DIV. CHAPMAN CHEMICAL CoO. MEMPHIS, TN 839 0 114 0 953 9 0 CONROE CREOSOTING CO. CONROE, TX 10 0 10 0 20 0 0 ATLANTIC WOOD INDUSTRIES PORTSMOUTH, VA 90 0 2 0 92 0 90 INC. J.H. BAXTER & CO. ARLINGTON, WA 500 0 0 0 500 0 755 BROOKS MFG. CO. BELLINGHAM, WA 5 0 0 0 5 0 250 OESER CO. BELLINGHAM, WA 5 0 0 0 5 0 0 PACIFIC WOOD TREATING RIDGEFIELD, WA 10 0 250 250 510 0 383 CORP. PACIFIC SOUND RESOURCES SEATTLE, WA 10 0 5 5 20 1 5 CASCADE POLE CO. TACOMA, WA 1 0 14 0 15 0 323 COWBOY TIMBER TREATING MandERSON, WY 0 0 0 0 0 0 0 INC. Totals 12,508 0 2,278 1,510 16,296 13 265,180 *Derived from TRI91 (1993) Post Office state abbreviations used “The sum of all released of the chemical to air, land, water, and underground injection wells by a given facility POTW = publicly-owned treatment works 3HNSOdX3 NYWNH HOH TVILN3LOd 'S JTON3IHJOHOTHOVINId oct PENTACHLOROPHENOL 121 5. POTENTIAL FOR HUMAN EXPOSURE and 12,000 pounds (5.5 metric tons) of pentachlorophenol, respectively, in their waste-water discharges to surface waters on an annual basis in the 1970s (EPA 1980f). Pentachlorophenol is no longer used in these applications (Pentachlorophenol Task Force 1993). Chlorination of phenolic compounds during water treatment has been reported to produce detectable levels of pentachlorophenol (Detrick 1977; Smith et al. 1976). In addition, common pesticides such as lindane, hexachlorobenzene, pentachlorobenzene, and pentachloronitrobenzene are known to be metabolized to pentachlorophenol by plants, animals, and/or microorganisms, but the contribution of metabolism of these pesticides to environmental levels of pentachlorophenol is unknown (Dougherty 1978). According to the TRI, an estimated total of 2,278 pounds of pentachlorophenol, amounting to 14% of the total environmental release, was discharged to water from manufacturing and processing facilities in the United States in 1991 (TRI91 1993) (Table 5-1). The data listed in the TRI should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.2.3 Soil - Pentachlorophenol is released to soils as a result of its past use as an herbicide, leaching from treated wood products, atmospheric deposition in precipitation, spills at industrial facilities using pentachlorophenol, and at hazardous waste sites. Most of the pentachlorophenol removed from effluent streams by wastewater treatment processes is adsorbed to sludge solids. Sludges from wood preservation industries historically have been estimated to contain up to 31,500 pounds (14.3 metric tons) of pentachlorophenol annually. Pentachlorophenol in solid wastes from wood-treatment facility evaporation ponds has been estimated to total an additional 133,000 pounds (60.2 metric tons) annually in the 1970s (EPA 1980f). However, most wood-treatment facilities have closed, or are in the process of closing, on- site evaporation ponds (Vulcan 1989). According to the TRI, an estimated total of 1,510 pounds of pentachlorophenol, amounting to 9% of the total environmental release, was discharged to soil from manufacturing and processing PENTACHLOROPHENOL 122 5. POTENTIAL FOR HUMAN EXPOSURE facilities in the United States in 1991 (TRI91 1993) (Table 5-1). TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.3 ENVIRONMENTAL FATE Pentachlorophenol released into the atmosphere from treated wood can be transported back to surface waters and soils via wet deposition. Atmospheric pentachlorophenol is transformed via photolysis; the compound is not expected to undergo free radical oxidation. In surface waters, pentachlorophenol undergoes biotransformation and photolysis. Hydrolysis, oxidation, and volatilization do not significantly affect surface water concentrations. Adsorption of pentachlorophenol in soils is pH dependent. The compound has a pK, value of 4.7 and consequently exists in ionic form at environmentally relevant pH values. For example, at pH 2.7, pentachlorophenol is about 1% ionized, whereas at pH 6.7, the compound is about 99% ionized (Crosby 1981). Adsorption decreases in neutral and basic soils and is strongest in acidic soils. Therefore, the compound is most mobile in neutral-to-basic mineral soils and least mobile in acidic organic soils. Biodegradation is a significant process under both aerobic and anaerobic conditions. Volatilization and photolysis do not appear to be important transport and transformation processes for pentachlorophenol in soils. 5.3.1 Transport and Partitioning A vapor pressure of 1x10 mm Hg has been reported for pentachlorophenol; the vapor pressure of the salt or ionic form of this compound is expected to be much less. Therefore, volatilization of the solvated anionic form from an aqueous system is not considered to be a significant transport mechanism under ambient conditions. Pignatello et al. (1983) reported that volatilization loss of pentachlorophenol as vapor and aerosol from treated river water in outdoor man-made channels was <0.006% of the initial test concentration. Volatilization of pentachloro- phenol from soil is also not expected to be a major transport pathway. Kilzer at al. (1979) determined the volatilization rates of pentachlorophenol from water and three soil types under laboratory conditions. The volatilization rates (expressed as percentage of applied pentachloro- phenol per mL evaporated water) from water, sand, loam, and humus were 2.57%, 0.13%, 0.31%, PENTACHLOROPHENOL 123 5. POTENTIAL FOR HUMAN EXPOSURE and 0.10%, respectively, in the 1st hour after application of 50 ppb pentachlorophenol. During the 2nd hour, the volatilization rates were 2.11%, 0.12%, 0.15%, and 0.12%, respectively. However, pentachlorophenol is volatilized from treated wood surfaces. Walls in a room treated with pentachlorophenol released the chemical into the air, with concentrations reaching 1 ng/m> on the 1st day after treatment and 160 ng/m> on the 4th day (Gebefugi et al. 1976). Pentachlorophenol is no longer used in the treatment of wood products intended for use in the interior of residences. Schellenberg et al. (1984) investigated the adsorption of chlorinated phenols by natural sediments and aquifer materials. These authors demonstrated that adsorption of pentachlorophenol was highly dependent on the organic content of the adsorbent. An average K,. of 32,900 was measured for pentachlorophenol in lake sediment, river sediment, and aquifer materials. The adsorption or mobility of pentachlorophenol in soils is controlled primarily by soil pH. The amount of pentachlorophenol adsorbed at a given pH increases with increasing organic content of the soil (Chang and Choi 1974). Pentachlorophenol is adsorbed to soil or sediment under acidic conditions, but the compound is mobile under neutral or alkaline conditions (Kuwatsuka and Igarashi 1975). Maximum adsorption has been reported at soil pH values of 4.6-5.1, with no adsorption above pH 6.8 (Choi and Aomine 1974). Pentachlorophenol can be leached from treated wood into surrounding soil. For example, Arsenault (1976) reported that pentachlorophenol migrated from the surface of utility poles to the adjacent soil, which had an average pentachlorophenol concentration of 654 ppm. However, mobility in soil was limited, as indicated by the average soil concentration of 3.4 ppm pentachloro- phenol at a distance of 12 inches from the poles. Veith et al. (1985) demonstrated that chemicals with a log K, value greater than 4.0 are likely to bioaccumulate in organisms and food chains. The log K, presented in Chapter 3 is 5.01, which suggests that pentachlorophenol will bioaccumulate to some degree. However, the extent of bioaccumulation will depend on the pH of the medium since pentachlorophenol converts at higher pH levels to the more water-soluble pentachlorophenate anion. Bluegill sunfish exposed to 0.1 mg/L pentachlorophenol accumulated the compound in various tissues to levels of 10-350 times the ambient water concentration in a 16-day static/renewal bioassay. PENTACHLOROPHENOL 124 5. POTENTIAL FOR HUMAN EXPOSURE Pentachlorophenol was rapidly eliminated upon transfer of the test organisms to clean water (Pruitt et al. 1977). Pentachlorophenol was reported to have a bioconcentration factor (BCF) of 81-461 in the soft tissue of a freshwater mussel; however, the compound was rapidly cleared by the test organisms (52% loss within 12 hours) (Makela et al. 1991). Other bioaccumulation tests with aquatic organisms include BCF values of 30-40 in carp muscle tissue and 300-400 in all other tissues (Gluth et al. 1985) and BCF values of 218 (whole fish) to 1,633 (fish lipid basis) for Juvenile American flagfish (Smith et al. 1990). In the latter test, which was a flow-through bioassay, the half-life of pentachlorophenol in the tissues was reported to be about 16 hours. Bioaccumulation of pentachlorophenol in algae, aquatic invertebrates, and fish (with BCFs of up to 10,000) has been demonstrated. Representative BCFs are as follows: goldfish, 1,000; polychaete, 3,830; bluegill sunfish, 13; blue mussel, 324; and eastern oyster, 78 (EPA 1986c¢). Biomagnification of pentachlorophenol in terrestrial or aquatic food chains has not been observed. In a 110-day study with rainbow trout, where pentachlorophenol was administered in the diet at a maximum concentration of 3,000 pg/kg, maximum concentrations of compound in fish tissues were 40 pg/kg after 50 days and 20 pg/kg at the end of the test period. In a 28-day depuration test, tissue half-life of the compound was about 7 days. According to the investigators, these results suggest that pentachlorophenol bioconcentration in fish occurs primarily through direct uptake from water rather than through ingestion of food. The similar pentachlorophenol tissue concentration levels of prey and predator salmonid fish from Lake Ontario were cited as additional evidence of the limited food chain bioaccumulation of the compound (Niimi and Cho 1983). Pentachlorophenol bioconcentration by earthworms has also been studied by several investigators. In 14-day exposure tests, BCFs of 3.4-13 were reported for uptake of pentachlorophenol adsorbed to soil particulates (Haque and Ebing 1988; van Gestel and Ma 1988). However, when bioconcentration was calculated on the basis of concentration of test compound in soil solution, BCF values of 426-996 were obtained (van Gestel and Ma 1988). PENTACHLOROPHENOL 125 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2 Transformation and Degradation 5.3.2.1 Air Atmospheric pentachlorophenol is probably photolyzed in the absence of water, although mechanisms for this reaction are not well known (Crosby and Hamadad 1971; Gab et al. 1975). Photolysis of sorbed or film-state pentachlorophenol in the presence of oxygen has also been observed (Gab et al. 1975). The reaction products were similar to those found in aqueous photolysis. No information was found regarding susceptibility of pentachlorophenol to free radical oxidation in the atmosphere. However, related compounds such as benzene, chlorobenzenes, and phenol have low reactivity with atmospheric hydroxy radicals; therefore, atmospheric oxidation of penta- chlorophenol is not expected. 5.3.2.2 Water Photolysis and biodegradation are believed to be the dominant transformation processes for pentachlorophenol in aquatic systems. Hydrolysis and oxidation are not important mechanisms for removal of the compound from surface waters. The molecular structure of pentachlorophenol is indicative of its stability to hydrolysis or oxidation (Callahan et al. 1979). Wong and Crosby (1981) reported no changes in pentachloro- phenol concentration in dark controls during their study of pentachlorophenol photodecomposition in water. Pentachlorophenol apparently did not hydrolyze in aqueous solutions at pH 3.3 or 7.3 when held at 26°C for up to 100 hours. Wong and Crosby (1981) reported that pentachlorophenol in aqueous solutions was photolyzed under laboratory ultraviolet (UV)-light irradiation with estimated half-lives of about 100 hours at pH 3.3 and 3.5 hours at pH 7.3. Photolysis of pentachlorophenol in aqueous solution following exposure to sunlight was also rapid; in laboratory experiments, concentrations of pentachloro- phenol in water were reduced from 9.3 ppm to 0.4 ppm in 24 hours and approached zero at the end of 48 hours (Arsenault 1976). In outdoor tests conducted with river water in man-made PENTACHLOROPHENOL 126 5. POTENTIAL FOR HUMAN EXPOSURE channels, Pignatello et al. (1983) demonstrated that photolysis of pentachlorophenol was rapid at the water surface (half-life of 0.70 hour at a depth of 0.5 cm). However, photolysis was greatly attenuated with increasing depth of the water column (half-life of 228 hours at a depth of 30 cm). Photolytic degradation accounted for a 5-28% decrease in the initial test concentration of the compound after 3 weeks. Pentachlorophenol is biotransformed in aqueous systems by acclimated microorganisms. Liu et al. (1981) found that acclimated cultures of activated sludge bacteria transformed pentachlorophenol more rapidly under aerobic conditions (half-life 0.36 days) than under anaerobic conditions (half- life, 192 days). Pignatello et al. (1983) reported that microbial transformation became the primary removal mechanism of pentachlorophenol added to river water in tests conducted in outdoor man-made channels. After about a 3-week acclimation period, microbial transformation accounted for a 26-46% decline in the initial test concentration of pentachlorophenol. In a follow-up study utilizing the same type of outdoor tests, Pignatello et al. (1985) found that biotransformation accounted for a 55-74% decrease in concentration of applied pentachlorophenol after a 3-5-week adaptation period. Biotransformation in the water column above sediments occurred at a greater rate under aerobic than under anaerobic conditions. Pentachlorophenol is degraded under anaerobic conditions in sewage sludge and sediments. After 6 months of operation, about 60% of the initial concentration of pentachlorophenol added to laboratory-scale, fixed-film reactors containing a digested municipal sewage sludge microbial inoculum was removed. Removal from reactors supplemented with glucose attained 98% of the initial charge over the same time frame. Trichlorophenol and tetrachlorophenol were observed as degradation products (Hendriksen et al. 1991). In other laboratory tests, reductive dechlorination of pentachlorophenol was found to be more rapid in freshwater sediments containing microbial communities adapted to dechlorinate 2,4-dichlorophenol and 3,4-dichlorophenol than in non- adapted sediment microbial communities. Degradation products identified included 2,3,5,6- tetrachlorophenol, 2,3,5-trichlorophenol, 3,5-dichlorophenol, 3-chlorophenol, and phenol (Bryant et al. 1991). In a study using radiolabeled pentachlorophenol, Arsenault (1976) demonstrated that the compound was transformed to carbon dioxide, water, and hydrochloric acid in an activated sludge treatment plant. On a pilot-plant scale, the same investigator also showed that a waste stream PENTACHLOROPHENOL 127 5. POTENTIAL FOR HUMAN EXPOSURE from a wood preserving facility containing 23 mg/L of pentachlorophenol could be treated successfully to produce a final effluent concentration of 0.4 mg/L of pentachlorophenol. In four simulated lentic environments, Boyle et al. (1980) tested the effects of dissolved oxygen, light, pH, and the presence of a hydrosoil (i.e., pond soil/sediment) on the transformation of pentachlorophenol. The persistence of pentachlorophenol was associated with three environmental variables: absence of light and hydrosoil; pH near or below pKa; and low oxygen concentration. Major reaction products were pentachloroanisole, 2,3,4,5-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, and 2,3,5,6-tetrachlorophenol. 5.3.2.3 Sediment and Soil Biodegradation is considered the major transformation mechanism for pentachlorophenol in soil. Pentachlorophenol is metabolized rapidly by most acclimated microorganisms (Kaufman 1978). Several cultures that degrade pentachlorophenol have been isolated from soil. Kirsch and Etzel (1973) obtained a mixed culture from a soil sample taken from the grounds of a wood product manufacturer. Using a continuous-flow enrichment technique, an unidentified bacterium which metabolized pentachlorophenol was identified as a sole source of organic carbon (Chu and Kirsch 1972). Edgehill and Finn (1983) added inocula of a strain of pentachlorophenol-acclimated Arthrobacter bacteria to soils in laboratory and enclosed outdoor tests. The soils were amended with 120-150 mg pentachlorophenol/L and 34 kg pentachlorophenol/hectare, respectively. In the laboratory test conducted in the dark at 30°C, the half-life of pentachlorophenol in inoculated samples was about 1 day, whereas the half-life in uninoculated samples was 12-14 days. Pentachlorophenol loss from uninoculated control plots in outdoor tests was 25% after 12 days at ambient temperatures (8-16°C), while losses from inoculated plots were 50-85%. Watanabe (1973) isolated a pentachlorophenol-decomposing Pseudomonas species (from soil perfused with pentachlorophenol solution) which was able to grow on and biotransform pentachlorophenol; all five chlorine atoms were released. Pseudomonas biotransformed ['4C]-pentachlorophenol rapidly and released radioactive carbon dioxide as well as the intermediate metabolites tetrachlorophenol and tetrachloro-hydroquinone. Tetrachloro-p-benzoquinone and 2,6-dichlorohydroquinone have also been implicated as metabolic intermediates for pentachlorophenol (Reiner et al. 1978). Several species of fungi have also been shown to transform pentachlorophenol (Cserjesi 1967, Cserjesi and Johnson 1972; Duncan and Deverall 1964). Radiolabeled pentachlorophenol added PENTACHLOROPHENOL 128 5. POTENTIAL FOR HUMAN EXPOSURE to three sterile soils was degraded by a white rot fungus (Phanerochaete chrysosporium) with half- lives of 0.5-3.8 days (Lamar et al. 1990). The compound has also been reported to be degraded by actinomycete bacteria (Middeldorp et al. 1990) and bacteria from the genus Flavobacterium (Seech et al. 1991). The rate of pentachlorophenol transformation in laboratory tests is more rapid in soils with high organic content than in those with low organic content, and greater when moisture content is high and soil temperature approaches the optimum for microbial activity (Young and Carroll 1951). Half-lives are usually on the order of 2-4 weeks. Pentachlorophenol degraded in a paddy soil at 28°C with a half-life of about 3 weeks; reducing conditions increased the rate of reaction slightly (Ide et al. 1972). Kuwatsuka and Igarashi (1975) confirmed these observations in 10 different soil types. Penta- chlorophenol biotransformation rates were higher under anaerobic (flooded) conditions than under aerobic (upland) conditions. It was shown that the half-life for pentachlorophenol under flooded conditions ranged from 10 to 70 days, while under upland conditions the range was 20-120 days, and the rate of reaction increased with the organic matter content. Pentachloro- phenol transformation was assumed to proceed by both chemical and microbial means, based on the effects of sterilization, soil temperature, and nature of the reaction products, which included pentachlorophenol methyl ether (pentachloroanisole), 2,3,4,5-, 2,3,4,6-, and 2,3,5,6- tetrachlorophenol, and 2,3,5-, 2,3,6-, and 2,3,4-trichlorophenol (or 2,4,5-trichlorophenol). 5.3.2.4 Other Media Laboratory studies were conducted to determine the effect of sunlight on concentrations of pentachlorophenol and chlorinated dibenzo-p-dioxins in wood treated with pentachlorophenol (Lamparski and Stehl 1980). Although chlorinated dibenzo-p-dioxins are known to be present in pentachlorophenol products as impurities, formation of OCDD as well as HpCDD and HxCDD was observed even when purified pentachlorophenol was irradiated. HxCDD and HpCDD were presumed to be degradation products of OCDD, not condensation products of tetrachlorophenol and pentachlorophenol. Evidence has recently been reported for the photolytic conversion of the OCDD contaminant of pentachlorophenol on soils to lower chlorinated dibenzo-p-dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Miller et al. 1989). PENTACHLOROPHENOL 129 5. POTENTIAL FOR HUMAN EXPOSURE 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT Pentachlorophenol historically has been widely detected in environmental media as a result of its widespread past use by industry, the agricultural sector, and the general public, cooling-tower algicide and fungicide, herbicide, molluscicide, paint preservative, plywood and fiberboard waterproofing agent, and drilling mud and photographic solution biocide. Pentachlorophenol is now regulated as a restricted-use pesticide. Therefore, it can only be purchased and used by certified applicators, and only for the applications covered by the applicator’ certification. Pentachlorophenol is no longer available to the general public. Although the compound has been detected in indoor air, surface waters, groundwater, drinking water, soils, rainwater, and a variety of foods in older monitoring studies, current contamination of these media by the compound is expected to be more limited given the restricted current usage of pentachlorophenol and its limited environmental persistence. 5.4.1 Air Limited information is available on the levels of pentachlorophenol in ambient air. EPA (19801) estimated atmospheric concentrations of pentachlorophenol using air models. A cumulative concentration estimate based on all emission sources was (.15-136 ng/m°. The lower end of this range coincides with the upper end of the range of computed air concentration estimates based on pentachlorophenol concentrations in rainwater in Hawaii (0.002-0.063 ng/m>) where penta- chlorophenol has been used extensively as an herbicide and wood preservative. 5.4.2 Water Of 497 surface water observations in EPA’s STORET database as of March 1979, 82% were at the detection limit; 84% of the remaining observations fell between 0.1 and 10 pg/L, with a total range of 0.01-100 pg/L (EPA 1979b). These data imply that ambient levels of pentachlorophenol in surface water are usually below 1 pg/L, with much higher levels in more industrialized areas. Pentachlorophenol levels monitored in surface water include the following: 0.1-0.7 pg/L in the Willamette River (Buhler et al. 1973); 9 pg/L in a river below a paper mill (Rudling 1970); 0.1-1 pg/L in the Great Lakes (EPA 1980f); <1 pg/L in a river at a sewage discharge site in PENTACHLOROPHENOL 130 5. POTENTIAL FOR HUMAN EXPOSURE Sacramento, California (Wong and Crosby 1978); 0.038-10.5 mg/L in a stream running through an industrial district in Pennsylvania (Fountaine et al. 1975); and 0.01-0.48 pg/L in streams in Hawaii (Young et al. 1976). Pentachlorophenol has also been detected in drinking waters at the following levels: 0.04-0.28 pg/L in Corvallis, Oregon (Buhler et al. 1973); a mean concentration of 0.07 pg/L in 108 samples surveyed by the National Organics Monitoring Survey (NOMS); and <1-800 ppb (an average of 227 ppb) in seven drinking water wells in Oroville, California (Wong and Crosby 1978). Pentachlorophenol was detected in raw effluent from a series of wood-treatment plants at levels ranging from 25 to 150 mg/L (Dust and Thompson 1972) and in influent (1-5 ppb) and effluent (1-4 ppb) at streams at a sewage plant in Corvallis, Oregon (Buhler et al. 1973). The compound has also been detected (concentrations unspecified) in surface-water and groundwater samples taken at a wood-treatment facility in Arkansas (McChesney 1988). 5.4.3 Sediment and Soil Although several investigators (Fountaine et al. 1975; Pierce and Victor 1978) refer to possible soil contamination as a source of pentachlorophenol levels in water samples, very little data are available on actual measurements of pentachlorophenol in soil. Arsenault (1976) reported penta- chlorophenol concentrations of 3.4-654 ppm in soil within 12 inches of treated utility poles. 5.4.4 Other Environmental Media Levels of pentachlorophenol in food are examined as a part of FDA’s on-going food monitoring studies. In 1973-1974, 10 out of 360 composite food samples contained pentachlorophenol at 0.01-0.03 ppm: 1 in dairy products, 1 in cereals, 1 in vegetables, and 7 in sugar (Manske and Johnson 1976). In the next year, 13 out of 240 composites contained pentachlorophenol (0.01-0.04 ppm), again mostly in sugars (Jansson and Manske 1977). Dougherty and Piotrowska (1976) reported that all of a series of random samples of Florida food contained pentachloro- phenol at levels of 1-1,000 ppb, principally in grain products. Pentachlorophenol was also PENTACHLOROPHENOL 131 5. POTENTIAL FOR HUMAN EXPOSURE detected at low levels in peanut butter (1.8-62 ppb) and chicken (6-12 ppb) (Farrington and Munday 1976). Pentachlorophenol concentrations in fish tissue for the years 1976-1979, reported in EPA’s STORET database, ranged from below the limit of detection to 50 mg/kg. Mean concentrations by region were as follows: Lake Michigan, 0.002 mg/kg; lower Mississippi, 0.478 mg/kg; Pacific Northwest, 16.38 mg/kg; Alaska, 5.0 mg/kg; Western Gulf, not detected; and south central lower Mississippi, not detected (EPA 1979b). Von Langeveld (1975) reported levels of pentachlorophenol ranging from 0.01 to 0.27 mg/L in 9 out of 65 samples of children’s paints in the Netherlands. It should be noted that the data discussed above are 13-17 years old (more recent data are not available). Use of pentachlorophenol has decreased in the intervening years because of restrictions placed on its use. Therefore, levels of pentachlorophenol found in other environmental media have presumably decreased since the time these data were published. 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Humans may be exposed to pentachlorophenol in occupational settings through inhalation of contaminated workplace air and dermal contact with the compound or with wood products treated with the compound. General population exposure may occur through contact with contaminated environmental media, particularly in the vicinity of hazardous waste sites. Important routes of exposure appear to be ingestion of contaminated groundwater used as a source of drinking water, ingestion of contaminated food and soils, and dermal contact with contaminated soils or products treated with the compound. In older residences constructed with treated wood products, inhalation of contaminated indoor air may also be an important source of exposure. In past years, pentachlorophenol has been detected in human adipose tissue, milk, blood, and urine. Data have been collected on pentachlorophenol levels in human urine, blood, adipose tissue, and cerebrospinal fluid for both occupational and non-occupational groups. While levels are much higher in occupationally exposed groups, tests on the general population consistently show evidence of low-level exposure. In an FDA study in Florida, Cranmer and Freal (1970) found an PENTACHLOROPHENOL 132 5. POTENTIAL FOR HUMAN EXPOSURE average pentachlorophenol urine level of 4.9 ppb in the general population, compared with 119.9 ppb in carpenters, boat builders, and spraymen. Bevenue and Beckman (1967) cite a range of 1,100-5,910 ppb (1.1-5.9 ppm) in the urine of Japanese pest control operators exposed to pentachlorophenol, compared with 10-50 ppb in non-exposed workers. Bevenue et al. (1967) compared results from a study in Hawaii on pentachlorophenol in urine of three groups; occupational, non-occupational, and a mixed population. The pentachlorophenol level of 1,802 ppb in the occupationally exposed population was almost 50 times higher than the non- occupational group level of 40 ppb. In more recent studies, Hill et al. (1989) detected penta- chlorophenol in 100% of urine samples taken from 197 children in Arkansas at a median concentration of 14 ppb. Pentachlorophenol was also found in 100% of urine samples taken from 50 members of the general population of Barcelona, Spain, at a mean concentration of 25 ppb (GOomez-Catalan et al. 1987). Among a group of 16 patients with neurological symptoms, pentachlorophenol was detected in blood serum and cerebrospinal fluid using a gas chromatograph with electron capture detection technique. Mean concentrations in these media were 22 pg/L (range, 4-60 pg/L) and 0.75 pg/L (range, 0.24-2.03 pg/L), respectively. Three people in the study group who reported contact with wood preservative products had the highest serum levels of pentachlorophenol. Cerebrospinal fluid levels were not correlated with serum levels or cerebrospinal protein levels (Jorens et al. 1991). The National Health and Nutrition Examination Survey II (NHANES II) and the National Human Adipose Tissue Monitoring Survey (NHATS) analyzed blood and urine specimens from approximately 6,000 persons in 64 communities throughout the United States for the presence of a number of compounds, including pentachlorophenol, during the period of 1976-1980. The initial results of the survey indicated that pentachlorophenol was detected in about 79% of urine samples tested (Murphy et al. 1983), and that pentachlorophenol-related phenols were also detected at lower frequencies. The mean pentachlorophenol value in urine samples tested during 1976-1979 was 6.3 ppb with the maximum level of 193 ppb (0.193 ppm) (Kutz et al. 1978). Pentachlorophenol measured in urine was considered to be the result of exposure to pentachloro- phenol, lindane, and hexachlorobenzene. More recent results of NHANES II indicate that pentachlorophenol was found in 71.6% of the urine samples collected from the general population at an estimated geometric mean concentration of 6.3 ng/mL. These results suggest PENTACHLOROPHENOL 133 5. POTENTIAL FOR HUMAN EXPOSURE that, during 1976-1980, almost 119 million individuals 12-74 years of age from the general population were exposed to pentachlorophenol. Males were found to have higher percentage quantifiable levels of pentachlorophenol and higher geometric mean concentrations in urine than females (Kutz et al. 1992). In a study of workers exposed to pentachlorophenol in the wood- preserving industry, Arsenault (1976) reported pentachlorophenol levels of 120-9,680 ppb in urine, with a mean concentration of 1,683 ppb. A mean pentachlorophenol blood serum level of 420 ppb was reported for residents of log homes, whereas a mean level of 40 ppb was reported for members of the general public with no known exposure to the compound. For residents of the log homes, pentachlorophenol serum levels of children were found to average 1.8 times those of their parents. Pentachlorophenol urine concentrations for residents of log homes averaged 69 ppb, whereas urine levels for the general population were found to be 3.4 ppb. Inhalation was believed to be the most likely route of exposure to pentachlorophenol in log homes (Cline et al. 1989). Pentachlorophenol was also found in serum samples taken from members of the general population of Barcelona, Spain, at a mean concentration of 21.9 ppb (Gomez-Catalan et al. 1987). In a separate study of 66 residents of log homes treated with pentachlorophenol in Kentucky, Hosenfeld et al. (1986) reported a geometric mean pentachlorophenol blood serum level of 47.6 ppb (0.048 ppm) and a geometric mean urine concentration of 21 pg per gram urinary creatinine. Pentachlorophenol was detected in blood and urine of all 66 residents. Mean pentachlorophenol blood serum levels in workers using pentachlorophenol or pentachloro- phenol-treated materials were found to range from 83 to 57,600 ppb by Cline et al. (1989). This upper limit is approximately 100 times the value expected from exposure to the TLV (Braun et al. 1979). Workers were involved in construction of log homes, repair of telephone lines, custodial care of log cabin museums, and in various operations in wood-preservative and chemical- packaging facilities. One worker from a chemical-packaging facility, with a whole blood pentachlorophenol level of 23,000 ppb, died (Cline et al. 1989). Shafik (1973) found a mean level of 26.3 pg/kg in adipose tissue from the general U.S. population and concluded that humans are continuously exposed to low levels of pentachlorophenol from the environment, food supplies and disinfectants. Geyer et al. (1987) investigated distribution and bioconcentration of pentachlorophenol in different tissues of humans. By comparing daily intake of pentachlorophenol with tissue concentrations, bioconcentration ratios of 5.7, 3.3, 1.4, 1.4, and PENTACHLOROPHENOL 134 5. POTENTIAL FOR HUMAN EXPOSURE 1.0 were obtained in liver, brain, blood, spleen, and adipose tissue, respectively. Pentachloro- phenol has also been found in human milk samples from West Germany at 0.03-2.8 pg/kg (Gebefugi and Korte 1983). In a study of human tissues removed at autopsy, including testes, kidney, prostate glands, livers, and adipose tissue, pentachlorophenol was found in all tissues examined at a range of 0.007 ppm (pg/g) in subcutaneous fat to 4.14 ppm in testes (Wagner et al. 1991). Based on the pentachlorophenol levels in their 1977 food survey, FDA estimated an average dietary intake of 0.76 mg/day for a typical 15-20-year-old male, and EPA (1978a) calculated an average dietary intake of 1.5 mg/day and a maximum dietary intake of 18 mg/day. However, the actual intake will be lower than estimates because average dietary intakes were based on mean concentration of positive samples. Considering pentachlorophenol levels in fish, peanut butter, food packaging materials, jar lids, etc., the average intake of pentachlorophenol in food has been estimated to be 1.5 mg/day (EPA 1980f). Daily dietary intake of pentachlorophenol from contaminated food has been estimated by another source to be 0.1-6 pg/day (WHO 1987). Using a six-compartment environmental partitioning model, Hattemen-Frey and Travis (1989) reported that the food chain is the most important source of exposure to pentachlorophenol for the general population. They estimated average daily dietary intake of the compound to be 16 pg/day from ingestion of contaminated food, primarily root vegetables. Pentachlorophenol was detected in 15% of the foods collected in eight market basket surveys from different regions of the United States during the period of April 1982 to April 1984 (Gunderson 1988). Foods representative of the diets of eight different age/gender population groups were prepared for consumption prior to analysis in a revision to FDA’s Total Diet Study methodology. Estimated mean daily intakes (ng/kg/day) of pentachlorophenol for these groups in 1982-1984 were as follows: (1) 6-11-month- old infants, 59.0; (2) 2-year-old children, 48.5; (3) 14-16-year-old females, 16.2; (4) 14-16-year-old males, 20.7; (5) 25-30-year-old females, 15.9; (6) 25-30-year-old males, 18.2; (7) 60-65-year-old females, 13.9; and (8) 60-65-year-old males, 15.5. Pentachlorophenol intakes (ng/kg/day) for three of these groups in 1988 were estimated in Total Diet Analyses to be as follows: (1) 6-11- month-old infants, 0.4; (2) 14-16-year-old males, 0.2; and (3) 60-65-year-old females, 0.3 (FDA 1989). In more recent surveys of pentachlorophenol exposure, food was found to be the most important source of intake for members of the general population (Coad and Newhook 1992; Wild and PENTACHLOROPHENOL 135 5. POTENTIAL FOR HUMAN EXPOSURE Jones 1992). In a multimedia analysis of pentachlorophenol exposure for the general population of Canada, food sources (mostly dairy products, grains and cereals) accounted for an estimated 74-89% of the total daily intake of pentachlorophenol. Inhalation exposure, especially of indoor air, accounted for an estimated 10-25% of total daily intake, whereas water and soil/household dust were found to be negligible sources. Daily exposure of recreational fishermen consuming about twice as much fish as members of the general population was estimated to be only about 2% higher than that of the general population. However, lifetime dietary intakes of pentachlorophenol for aboriginal subsistence fishermen relying on traditional diets of fish and fish products were estimated to be about twice those of members of the general Canadian population (Coad and Newhook 1992). In the United Kingdom, dietary sources are believed to account for greater than 90% of the estimated total daily intake of 5.7 pg pentachlorophenol/day by members of the general population. This value is considerably smaller than the 39 pg/day estimate for occupationally exposed individuals. Inhalation is believed to be the most important route of exposure in workplace settings (Wild and Jones 1992). In a study that used the clearance concept to estimate net daily intake (i.e., net daily intake = clearance x average steady state concentration in plasma), the net daily intake of pentachlorophenol for members of the U.S. general population not specifically exposed to the compound was estimated to be 12.3-135.9 pg/day. For members of the U.S. general population residing in log homes, net intake was estimated to be 140-157 pg/day. Daily intake estimates for occupationally exposed individuals varied widely depending on the type of work involved; estimates ranged from 35 to 24,000 pg/day (Reigner et al. 1992a). The National Organic Monitoring Survey conducted in 1976 found pentachlorophenol residues in 86 of 108 drinking water samples, with a mean of 0.07 pg/L (ppb) and a maximum of 0.7 pg/L (ppb) (EPA 1978a); however, the median concentration was less than 0.01 pg/L (ppb), the minimum detectable limit. In another survey, pentachlorophenol was detected at 1.3-12.0 pg/L (ppb) in 8 out of 135 systems surveyed (EPA 1980a, 1980c). Assuming an intake of 2 L of drinking water/day, exposure for most people would be less than 0.02 pg/day, while the maximum exposure would be 24 pg/day. Inhalation of estimated ambient levels of pentachlorophenol in the atmosphere has an associated exposure level of 6 pg/day for the general population (EPA 1980f). Subpopulations in the vicinity of pentachlorophenol sources and workers may be exposed to significantly higher levels. For example, workers in the vicinity of a cooling tower may have been exposed to 14.4 mg PENTACHLOROPHENOL 136 5. POTENTIAL FOR HUMAN EXPOSURE pentachlorophenol/day, and those in wood-treatment plants may have been exposed to 0.9-14 mg pentachlorophenol/day (EPA 1980f). Pentachlorophenol levels in the air of an experimentally treated room varied greatly (1-160 pg/m>) with temperature and ventilation (Gebefugi et al. 1976). Pentachlorophenol was detected at a geometric mean concentration of 0.080 ng/L (7.3 ppb) in 62 of 63 air samples taken in 21 log homes treated with the compound. The homes, all located in Kentucky, were categorized into six treatment types: (1) "never treated"; (2) external treatment; (3) manufacturer treated; (4) treated and sealed; (5) treated, sealed, and neutralized; and (6) treated and neutralized. Concentrations in "never treated" homes, which were lower than those in treated homes, were believed to be the result of application of pentachlorophenol to logs during storage to prevent fungal growth. Treated logs were found to be the source of penta- chlorophenol in indoor air; air concentrations were highly correlated with pentachlorophenol concentrations in wood cores (geometric mean 15,900 ng/g wood) and log surface wipes (geometric means 89.6 and 187 ng/100 cm?) (Hosenfeld et al. 1986). Concentrations of pentachlorophenol in older structures built with pressure-treated wood brushed with pentachlorophenol were reported to range from 0.5 to 10 pg/m? (EPA 1984). Use of sealers decreased this concentration by 85%. Indoor air interiors of structures built with industrially dipped non-pressure-treated wood were reported to contain levels of pentachlorophenol that ranged from 34 to 104 pg/m> (EPA 1984). Logs used for home construction are no longer treated with pentachlorophenol. Dermal absorption is another potential exposure pathway. Little information is available regarding permeability of skin to pentachlorophenol. EPA (1984) has assumed a dermal absorption efficiency in humans of 50% for pentachlorophenol in organic solvents and 10% for an aqueous solution of sodium pentachlorophenate. Dermal exposure is potentially an occupational problem; the general public is not expected to be exposed to pentachlorophenol via dermal contact. Santodonato (1986) suggested that dermal contact is the most important route of occupational exposure to pentachlorophenol because of the manner in which the compound is used (i.e., manual handling of solutions and treated materials) and its low vapor pressure. Workers such as carpenters, lumber-yard workers, and loading-dock laborers handling treated materials could be exposed continually via this route as well as by inhalation. The potential for dermal exposure to pentachlorophenol at hazardous waste sites is unknown. PENTACHLOROPHENOL 137 5. POTENTIAL FOR HUMAN EXPOSURE The National Occupational Hazard Survey (NOHS), conducted by the National Institute for Occupational Safety and Health (NIOSH), estimated that 179,243 workers in 22,347 plants were potentially exposed to pentachlorophenol in the workplace in 1970 (NIOSH 1976). The largest numbers of exposed workers were employed in the following fields: general building contractors; special trade contractors; chemicals and allied products industries; electric, gas, and sanitary services; and medical and other health services industries. Preliminary data from a second workplace survey, the National Occupational Exposure Survey (NOES) conducted by NIOSH from 1980 to 1983, indicated that 26,463 workers (including 3,916 women) in 1,490 plants employed in lumber and wood products, business services, wholesale trade, general building contractors, and chemicals and allied products industries were potentially exposed to pentachlorophenol in the workplace in 1980 (NIOSH 1984a). Most of these workers were pest controllers, electrical poser installers and repairers, laborers, assemblers, carpenters, miscellaneous precision workers, janitors, engineers, and engineering technicians. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Pentachlorophenol levels in human tissues are much higher in occupationally exposed groups than in the general public. Populations with potentially high exposure include individuals involved in the manufacture and use of the compound. Residents near pentachlorophenol manufacturing plants, and wastewater treatment sludge disposal sites may also be exposed to the chemical at higher concentrations than the general public. Residents around the 246 NPL sites known to have pentachlorophenol contamination may also be exposed to the chemical at higher levels in contaminated environmental media. Pentachlorophenol is found as a residue in treated wood that has been preserved with this chemical. Examples of consumer items containing pentachlorophenol-treated wood have included boats, furniture, and log homes. In fact, some families living in homes historically treated with pentachlorophenol have been reported to have symptoms of chronic exposure (Jagels 1985). Since the compound is no longer used in the treatment of wood products for log homes, outdoor furniture, or playground equipment, human exposure from these sources is probably limited to contact with materials treated in the past. PENTACHLOROPHENOL 138 5. POTENTIAL FOR HUMAN EXPOSURE 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of pentachlorophenol is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of pentachlorophenol. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical/chemical properties of pentachlorophenol are well characterized (see Chapter 3). Production, Import/Export, Use, Release, and Disposal. Pentachlorophenol is currently being produced by only one manufacturer (SRI 1991). Current production volume data are not available; however, it is known that production volumes steadily decreased from 45 million pounds in 1983 to 32 million pounds in 1986 (Mannsville 1987). Pentachlorophenol was, in the past, one of the most heavily used pesticides in the United States but is now regulated as a restricted use pesticide (CELDS 1992; EPA 1984). The compound is found in all environmental media as a result of its past widespread use. The only disposal method located in the literature is incineration, which releases polychlorinated dibenzo-p-dioxins and dibenzofurans at unspecified levels (Karasek and Dickson 1987). Disposal of pentachlorophenol is subject to EPA restrictions (EPA 1991a, 1991b). PENTACHLOROPHENOL 139 5. POTENTIAL FOR HUMAN EXPOSURE According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1991, became available in May of 1993. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Environmental Fate. Information on environmental fate of pentachlorophenol is sufficient to permit a general idea of transport and transformation of the chemical in the environment. The compound is expected to partition to soils and sediment, and to be transported in surface water and groundwater. Pentachlorophenol is transformed by photolysis (Wong and Crosby 1981) and biodegradation (Lamar et al. 1990; Liu et al. 1981; Pignatello et al. 1983; Seech et al. 1991). More information on rates of photolysis and biotransformation under various environmental conditions would improve current understanding of pentachlorophenol’s environmental fate. Information on the fate of pentachlorophenol in groundwater would also be helpful. Bioavailability from Environmental Media. Pentachlorophenol is readily and completely absorbed following inhalation, oral, and dermal exposure (Braun et al. 1979; Casarett et al. 1969; Cline et al. 1989; Hosenfeld et al. 1986; Jones et al. 1986; Uhl et al. 1986). Additional information on the bioavailability of pentachlorophenol adsorbed to soils would be helpful in assessing the relative importance of ingestion of contaminated soils as a potential route of human exposure. Food Chain Bioaccumulation. Pentachlorophenol is bioconcentrated by terrestrial and aquatic organisms (EPA 1986c; Makela et al. 1991; Smith et al. 1990). However, biomagnification of the compound in terrestrial and aquatic food chains has not been demonstrated as a result of the fairly rapid metabolism of the compound by exposed organisms (Niimi and Cho 1983). The food chain bioaccumulation potential of pentachlorophenol can currently be characterized without generation of additional data. Exposure Levels in Environmental Media. Pentachlorophenol has been detected in ambient air, surface water, drinking water, soils, and foods. Estimates of dietary intake of the compound have been made by the World Health Organization (WHO 1987), EPA (EPA 1978a), and FDA (FDA 1989; Gunderson 1988). PENTACHLOROPHENOL 140 5. POTENTIAL FOR HUMAN EXPOSURE Reliable monitoring data for the levels of pentachlorophenol in contaminated media at hazardous waste sites are needed so that the information obtained on levels of pentachlorophenol in the environment can be used in combination with the known body burden of pentachlorophenol to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. Exposure Levels in Humans. Pentachlorophenol has been measured in blood, urine, cerebrospinal fluid, and tissues of humans (Bevenue et al. 1967; Hill et al. 1989; Jorens et al. 1991). Quantitative data that correlate varying levels in the environment with levels in body fluids and health effects are not available. This information does exist for residents of log homes treated with pentachlorophenol; levels in blood and urine were highly correlated with levels in indoor air. Additional information on exposure levels for populations living near hazardous waste sites would be helpful. This information is necessary for assessing the need to conduct health studies on these populations. Exposure Registries. No exposure registries for pentachlorophenol were located. This substance is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to exposure to this substance. 5.7.2 On-going Studies As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environment Health Laboratory Sciences Division of the National Center for Environment Health and Injury Control, Centers for Disease Control, will be analyzing human urine samples for pentachlorophenol and other phenolic compounds. These data will give an indication of the frequency of occurrence and background levels of these compounds in the general population. The U.S. Department of Agriculture is sponsoring several studies on degradation, adsorption, and uptake of pentachlorophenol. For example, research is being conducted at the University of Idaho on the use of Flavobacterium ATCC 39723 for on-site detoxication of pentachlorophenol PENTACHLOROPHENOL 141 5. POTENTIAL FOR HUMAN EXPOSURE containers and rinsates. At Cornell University, a study is underway to examine adsorption and oxidative degradation of organic compounds, including pentachlorophenol, at soil mineral surfaces. Uptake of pentachlorophenol by crops in sludge-amended soils is under study at New Mexico State University. In addition, on-going remedial investigations and feasibility studies at NPL sites known to be contaminated with pentachlorophenol should add to the available database for environmental levels, environmental fate, and human exposure. PENTACHLOROPHENOL 143 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring pentachlorophenol, its metabolites, and other biomarkers of exposure and effect to pentachlorophenol. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS Exposure to pentachlorophenol is most commonly evaluated by analysis of urine, blood, feces, or adipose or other tissues, using gas chromatography (GC) combined with electron capture detection (ECD) or high-performance liquid chromatography (HPLC) combined with ultraviolet (UV) detection. Recovery is generally high and sensitivity using GC/ECD and HPLC/UV is in the parts per billion (ppb) range. Some efforts are currently in development to detect penta- chlorophenol metabolites in urine as a biological marker. Many purification schemes take advantage of the fact that pentachlorophenol is a weak organic acid. These methods involve extracting the compound into the organic phase under acidic conditions, and/or extracting into alkaline solution as phenolate salts (Chou and Bailey 1986; EPA 1986b). Thus the standard methods involve multiple extractions, with potential for sample loss; some of these methods derivatize pentachlorophenol prior to analysis (EPA 1980b; NIOSH 1984b). Derivatization often involves diazomethane or diazoethane, which are toxic substances (Bevenue et al. 1968; Holler et al. 1989; Morgade et al. 1980; Shafik 1973; Wagner et al. 1991). Recent methods have tried to simplify the purification scheme and avoid using toxic chemicals for derivatization (Maris et al. 1988). PENTACHLOROPHENOL 144 6. ANALYTICAL METHODS In an effort to use less toxic materials, blood and urine samples were derivatized with acetic anhydride (Needham et al. 1981). The detection limit was 1-2 ppb using GC/ECD. Penta- and tetrachlorophenols were analyzed simultaneously in urine using HPLC (Pekari and Aito 1982). This method was used for three years in Finland in the biological monitoring of workers exposed to chlorophenols. It is more rapid than GC and does not involve the use of benzene, diazomethane, or pyridine, which pose health risks to the analyst. A rapid extraction method followed by GC/ECD had a detection limit of 0.5 ppb (Kalman 1984). Because pentachlorophenol exists in urine as both free pentachlorophenol and conjugated penta- chlorophenol (glucuronide and sulfate), hydrolysis of urine is necessary to determine total pentachlorophenol (Edgerton and Moseman 1979; Pekari et al. 1991). Acid hydrolysis is preferable to enzymatic hydrolysis because the pentachlorophenol metabolite TCHQ is an inhibitor of B-glucuronidase (Drummond et al. 1982). Although pentachlorophenol and other chlorinated phenols are stable in frozen urine samples, they are degraded by repeated thawing and refreezing (Edgerton 1981). Acid hydrolysis followed by reverse phase HPLC/UV and GC/ECD have been used to measure total pentachlorophenol in urine of people occupationally exposed to pentachlorophenol (Drummond et al. 1982; Pekari et al. 1991). The detection limits for HPLC/UV and GC/ECD were 0.2 ppm and 0.01 ppm, respectively, which are sufficiently sensitive to detect occupational exposure. Using a simplified method without derivatization, total pentachlorophenol and free pentachlorophenol were measured in plasma and urine, with a detection limit of 1.5 pg (Rick et al. 1982). This modification shortens analysis time and allows the use of GC/ECD which increases sensitivity. The pentachlorophenol metabolites, TCHQ and tetrachloropyrocatechol, were identified in human urine samples using GC/MS (Edgerton et al. 1979). The detection limit was 1 ppb and recovery was about 95%. Pentachlorophenol and TCHQ were also detected using a cheaper GC/ECD method following a simple extraction (Reigner et al. 1990), but the detection limit was at least 50 ppb. Negative chemical ionization (NCI) mass spectrometry was used to detect pentachlorophenol in human serum (Kuehl and Dougherty 1980). The NCI mass spectrometer was reported uniquely suited for screening partially purified samples. High sensitivity was obtained by dansylating purified compound and using HPLC ultraviolet (UV) detection (de Ruiter et al. 1990). PENTACHLOROPHENOL 145 6. ANALYTICAL METHODS Hexane extraction, cleanup on thin layer chromatography (TLC) plates, and HPLC/UV detection were used to isolate and characterize pentachlorophenol in human fat, demonstrating that penta- chlorophenol is present in human adipose tissue as an ester of palmitic acid (Ansari et al. 1985). Fatty acid conjugates of pentachlorophenol and other chlorinated phenols could be separated by reverse-phase HPLC (Kaphalia 1991). TLC followed by GC/ECD was used to analyze pentachlorophenol in adipose tissue (Ohe 1979). GC/ECD has been used to quantify pentachlorophenol residues in tissues (Wagner et al. 1991). The sensitivity of this method is in the sub-ppm range; >100% recoveries were obtained. GC/MS (NCI) was then used to confirm the identity of the pentachlorophenol residues in the samples. Precision data were not reported. Analytical methods for determining pentachlorophenol in biological fluids and tissues are shown in Table 6-1. 6.2 ENVIRONMENTAL SAMPLES Concerns about contamination of environmental media, plants, and animals with pentachloro- phenol have led to the need for more rapid, sensitive, and selective methods of analysis. As with biological samples, the most common methods of analysis are GC/ECD, high resolution gas chromatography (HRGC)/GC, and HPLC/UV detection. Under EPA’s Contract Laboratory Program for semivolatiles such as pentachlorophenol, the Contract Required Quantitation Levels (CRQL) for water and low soil sediments are 50 mg/L (50 ppm) and 160 mg/kg (160 ppm), respectively (EPA 1986a). Methods are available that detect pentachlorophenol in water or sediment at the 1-10-ppb range. Pentachlorophenol could be detected in marine water at concentrations ranging from 0.2 to 200 ppb in volumes as small as 5 mL using a simplified monitoring procedure with HPLC/UV detection (Giam et al. 1980). This method reduces costs and analysis time and can also be used in other aquatic toxicity studies. Differential pulse polarography was used for direct determination of trace amounts of pentachlorophenol (Wade et al. 1979). It was demonstrated that pentachlorophenol is electrochemically reduced and direct determinations are possible at levels as low as 0.27 ppm. TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Blood Blood Blood Serum Extract with hexane; elute pentachloroanisole with benzene in hexane Extract with benzene and convert PCP to its methylether derivative Add H,SO, and benzene to the sample and stir while heating; centrifuge; collect benzene layer, evaporate and add diazomethane to make methyl ether derivative Acidify with phosphoric acid; elute from reverse- phase column with dichloromethane; dansylate; concentrate GC/ECD GC/ECD GC/ECD LC/UV 1 ppb 10 ppb 20 ppb 0.4 ppb 90% 92% 87-100% 85% NIOSH 1984b (method 8001) EPA 1980b Bevenue et al. 1968 de Ruiter et al. 1990 SAOHL3W TVOILATVYNY 9 TON3IHdJOHOTHOVIN3d avi TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Serum Serum, urine Plasma, urine Urine Acidify sample to pH 1 with hydrochloric acid; extract with dichloromethane; concentrate; derivatize with diazoethane; clean up using silical gel GC/ECD Acidify to pH 2 with HCI, digest at 100°C, extract with toluene GC/ECD Sample collected into tubes containing EDTA and ascorbic acid; plasma mixed with citrate buffer, pH 3, extracted with diethyl ether, and concentrated. Urine was buffered with phosphate buffer pH 7.4 and processed as above. GC/ECD Extract with benzene; add hexane; elute pentachloroanisole with benzene in hexane GC/ECD 0.03 ppm 0.5 ppb 100 ppb (urine); 50 ppb (plasma) 1 ppb 99% 105% (urine); 80% (serum) 89-93% 94.7% Morgade et al. 1980 Kalman 1984 Reigner et al. 1990 NIOSH 1984b (method 8303) SAQOH.L3W TVOLLATYNY 9 JON3IHJOHOTHOVINId yl TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Urine Urine Urine Urine Acidify urine; hydrolyze; extract with benzene; methylate phenolic group Add HCl to sample; boil; extract with hexane /isopropanol; centrifuge; dry; collect residue in methanol/water Add HCI to sample; boil; extract with hexane /isopropanol; centrifuge; back extract to basic borate buffer; derivatize with acetic acid anhydride and pyridine Acidify with HCI; boil; add Na bisulfite; centri- fuge; extract with benzene GC/ECD HPLC/UV GC/ECD GC/ECD 5 ppb 26 ppb 0.01 mg/L <1 ppb 90% 84% No data 91-97% EPA 1980b Pekari and Aitio 1982 Pekari et al. 1991 Edgerton et al. 1979 SAOHL3W TVOILATYNY 9 TONIHJOHOTHOVIN3d svi TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Urine Urine Urine Urine Urine Add H,SOy; collect distillate and add NaCl and NaOH; acidify aqueous layer; extract with methylene chloride Add HCI to sample; extract twice with benzene; add hexane Add internal standard to sample; mix Acidify with H,SO,; extract with hexane Acid hydrolysis; extract with benzene; derivatize with diazoethane; column clean up RPHPLC/UV GC/ECD HPLC/UV GC/ECD MS (NCI) 0.2 ppm <10 pg 0.25 ppm 1.5 pg 1 ppb >85% 88% 89-96% 102% ~100% Drummond et al. 1982 Siqueina and Fernicola 1981 Chou and Bailey 1986 Rick et al. 1982 Holler et al. 1989 SAOHLIW TVOILATYNY 9 JTON3HdOHOTHOVLIN3d 514% TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Body fluids Acidify sample and GC/ECD extract with hexane; add acetic anhydride; wash with boric acid/NaOH Human semen Macerate sample/tissue ~~ MS (NCI) and adipose tissue with sulfuric acid, com- plete steam distillation; concentrate organic layer Adipose tissue Grind tissue; add hex- GC/ECD ane; add NaOH; extract with hexane; add concentrated HCI; extract with diethyl ether; mix; add diazo- ethane; concentrate; add hexane and anhydrous sodium sulfate; analyse hexane layer Adipose tissue Homogenize sample; GC/ECD rehomogenize in hexane; combine supernatants; separate extracted fat on TLC; scrape appropriate area and suspend in hexane; evaporate 1-2 ppb low ng S ppb 5 ppb No data >90% 75% 85-98% Needham et al. 1981 Kuehl and Dougherty 1980 Shafik 1973 Ohe 1979 SAOHL3N TYOILATVYNY 9 TON3IHJOHOTHOVINId 0st TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Adipose tissue Feces Liver Preparation method Add hexane; GC/ECD homogenize; add aqueous sodium hydroxide; extract with hexane; add diethyl ether; extract; derivatize with diazoethane Collect sample into GC/ECD tubes containing EDTA and ascorbic acid; acidify in warm sulfuric acid, extract with diethyl ether; concentrate Homogenize; incubate LC/ECD with sulfuric acid at 100°C; extract with hexane /toluene Analytical method Sample detection limit 0.14 ppm 100 ppb 1.5 ppb Percent recovery 91% No data 60-70% Reference Morgade et al. 1980 Reigner et al. 1990 Maris et al. 1988 SAOHL3W TVYOILATYNY 9 TON3IHJOHOTHOV.LIN3Id St TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample matrix Preparation method Analytical method Fat, liver, muscle, serum Fat: homogenize with HCI; extract with ethyl acetate-hexane; elute from florisil chloro- phenol with methanol- chloroform Other tissues: homogenize; reflux with Na,SO, and NaOH; add TBAH and ether extract; concentrate extract; elute from silica column with methanol chloroform RPHPLC/UV Sample detection Percent limit recovery Reference <0.1 ppm 73-108% Mundy and Machin maximum 1981 SAOH.L3W TVOILATYNY 9 TON3HJOHOTHOVINId 2st TABLE 6-1. Analytical Methods for Determining Pentachlorophenol in Biological Materials (continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Tissues (testes, Homogenize tissue GC/ECD; GCMS (NCI) 0.004 ppm 115% Wagner et al. 1991 kidney, prostate, sample, extract with liver, and hexane/propanol and omentum fat) centrifuge; remove hexane layer; repeat extraction twice; partition into potassium hydroxide; acidify aqueous layer; extract with hexane; derivative with diazomethane; clean up on Florisil column; elute with hexane; additional clean up on activated silica gel column; elute with benzene in hexane ECD = electron capture detection; EDTA = ethylendiaminetetraacetic acid; GC = gas chromatography; HCI = hydrochloric acid; HPLC = high performance liquid chromatography; H,SO, = sulfuric acid; LC = liquid chromatography; MS = mass spectrometry; Na = sodium; NaCl = sodium chloride; NaOH = sodium hydroxide; Na,SO, = sodium sulphate; NCI = negative chemical ionization; PCP = pentachlorophenol; RPHPLC = reverse phase high performance liquid chromatography; TBAH = tetrabutyl- ammonium hydroxide; TLC = thin layer chromatography; UV = ultraviolet detection SAOH.LIN TVOILATVYNY 9 JTON3IHJOHOTHOVIN3d £61 PENTACHLOROPHENOL 154 6. ANALYTICAL METHODS HPLC/UV was used to distinguish among 10 different phenolic compounds at mg/L levels in water (Realini 1981). HPLC/UV was also used to measure chlorinated phenols in surface-treated lumber and to distinguish between tetra- and pentachlorophenol (Daniels and Swan 1979). Automated HPLC is 10 times faster than wet chemical techniques. Once the method for analysis has been established and tested thoroughly, the HPLC method requires neither extensive pre- treatment nor highly trained laboratory personnel (Ervin and McGinnes 1980). For relatively clean water samples, HPLC offers a rapid and sensitive method, but its advantages are lost when a complex matrix such as municipal wastewater has to be analyzed (Buisson et al. 1984). The resolution possible with capillary gas chromatography and the selectivity of the ECD towards halogenated compounds make HRGC/ECD the method of choice for the detection and quantification of chlorinated phenols at trace levels in complex matrices. Derivatization with a halogen-containing reagent enhances the ECD response. For measuring pentachlorophenol in wastewater using HRGC/ECD, sensitivity is in the ppt range. Recoveries are adequate and precision is good. Similar results were obtained in a comparison of HPLC and GC techniques for determination of pentachlorophenol in animal materials (Mundy and Machin 1981). Pentachlorophenol could be separated from acidic pesticides and other organic acids possibly present in a mill effluent by extraction with an acetylating agent (Rudling 1970). A similar single step extraction and acetylation procedure was used to determine several chlorinated phenolic compounds in paper mill effluent without interference (Lee et al. 1989). GC/MS has been used to measure pentachlorophenol in honey (Muifio and Lozano 1991). This method is simple, accurate, and rapid. Sensitivity is in the low-ppb range. Good recoveries (84-102%) and precision (2.8-6.3% relative standard deviation [RSD]) were obtained. A study comparing several methods for rapidly extracting pentachlorophenol from water or soil reported high recovery from all methods using HPLC/UV (Wall and Stratton 1991). A method combining extraction with derivatization by acetic anhydride had a detection limit of about 0.1 ppb for GC/ECD (Xie 1983). PENTACHLOROPHENOL 155 6. ANALYTICAL METHODS Immunochemical personal exposure monitors (PEMs) are currently being developed for assaying pentachlorophenol sampled from ambient air (Hall et al. 1992). This method is highly selective and involves direct, antibody-based sampling of analytes from air with subsequent quantitation of the analyte by enzyme immunoassay. The lower limit of detection for measuring pentachloro- phenol in the assay is approximately 0.5 ng/mL. Recovery and precision data were not reported. Methods for analyzing pentachlorophenol in environmental samples are shown in Table 6-2. 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of pentachlorophenol is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of pentachlorophenol. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Methods are available to detect and quantify pentachlorophenol in blood, urine, feces, and tissue (Bevenue et al. 1968; Chou and Bailey 1986; de Ruiter et al. 1990; Drummond et al. 1982; Edgerton et al. 1979; EPA 1980b: Holler et al. 1989; Kalman 1984; Kuehl and Dougherty 1980; Maris et al. 1988; Morgade et al. 1980; Mundy and Machin 1981; Needham et al. 1981; NIOSH 1984b; Ohe 1979; Pekari and Aitio 1982; Pekari et al. 1991; Reigner et al. 1990; Rick et al. 1982; Shafik 1973; Siqueina and Fernicola 1981; Wagner et al. 1991). Sensitivity is high and recovery is good; these methods can TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Stack samples Waste water Water Extract sample with hex- ane; derivatize with ace- tic anhydride, collect or- ganic layer; concentrate Air samples collected in PEM Es; analyte diffuses across semipermeable membrane into antibody reservoir; analyte is bound by antibody in PEM; antibody is removed from PEM device and quantified by enzyme immunoassay Acidify waste water sample with H,SO,; extract with chloroform Acidify sample with HCI; extract with methylene chloride GC/MS ELISA HPLC/UV HPLC/UV No data 0.5 ng/mL 11 ppb 1 ppm 80-104% No data No data 90% Cuiu et al. 1986 Hall et al. 1992 Ervin and McGinnis 1980 Realini 1981 SAOHL3N TVOLLATVYNY 9 TON3IHJOHOTHOVIN3d 961 TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples (continued) Sample matrix Water, mill effluent Pulp mill effluent Marine water Seawater Preparation method Acidify sample with H,SO,; extract with hexane; extract organic phase with borax; add hexane, acetylate, and analyse the organic phase Extract onto solid phase sorbents; elute with acetonitrile Take 5 ml water and acidify with H,SO,; extract with petroleum ether/diethylether; evaporate solvent; dissolve residue in CH,CN; measure at 254 nm Acidify sample, add chloroform and shake; add NaOH to chloro- form extract; read aqueous fraction at 320 nm Analytical method GC/ECD LC-ED HPLC/UV UV spectrophotometry Sample detection limit 0.1 ppb No data 0.2 ppb 5-50 ppb Percent recovery 84-93% >100% 84% 92-102% Reference Rudling 1970 Butler and Dal Pont 1992 Giam et al. 1980 Carr et al. 1982 SAOHL3W TVOILATYNY 9 7TON3IHJOHOTHOV.IN3d St TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Drinking water Waste water Water and waste water Acidify water sample; extract with dichloromethane and hexane; derivatize with diazoethane; clean up on silica gel Acidify to pH <2; ex- tract with methylene chloride; exchange into 2-propanol. For ECD, derivatize with penta- fluorobenzyl bromide Homogenize with dichloromethane; clean up by sample concentration; back extract with alkali; derivatize by extractive alkylation with pentafluorobenzoyl chloride GC/ECD GC/FID GC/ECD HRGC/ECD 0.3 ppm 7.4 ppm 0.59 ppm 5 ng/L 64% 36-134% 36-134% 64-80% Morgade et al. 1980 EPA 1986b (method 8040) Buisson et al. 1984 SAOHL3N TVYOILATVYNY 9 TON3IHJOHOTHOVIN3d 8G1L TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Effluent Sludge /soil Sediment Mix sample with potassium carbonate, acetic anhydride, and petroleum ether; dry organic layer and concentrate Add Na,SOy,; Soxhlet extract using toluene/ methanol or acetone/ hexane; acid-base partition clean up. For ECD, derivatize with pentafluorobenzyl bromide Mix with sodium carbo- nate with or without hexane (“pretreatment”); discard organic phase if present; derivatize by adding acetic anhydride in hexane; centrifuge GC/ECD GC/FID GC/ECD GC/ECD <0.6 ppb 7.4 ppm 0.59 ppm ~0.1 ppb 92-104% 36-134% 36-134% 96-99% (without pretreat- ment); 89% (with pre- treat- ment) Lee et al. 1989 EPA 1986b (method 8040) Xie 1983 SAOHL3W TVOILATYNY 9 TON3HJOHOTHOVIN3d 651 TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples (continued) Sample matrix Soil Surface-treated lumber Preparation method (1) Soxhlet extract in ethanol/toluene. (2) Ex- tract with hexane /ace- tone acidified to pH 2 with HCI; centrifuge. (3) Add water to sample and acidify with HCI; ultrasonically extract with hexane /acetone; centrifuge. (4) vortex extract with acetonitrile; centrifuge; dry extracts and dissolve in acetoni- trile. HPLC/UV Grind dried lumber sample; extract with acetonitrile containing p-bromophenacyl deri- vative of BB-dimethyl- anyhic acid HPLC/UV Analytical method Sample detection limit No data 0.1 mg/cm? Percent recovery Reference (1) 943- Wall and Stratton 1991 98%; (2) 94.8- 97.8%; (3) 94.4- 98.5%; (4) 96.1- 100% No data Daniels and Swan 1979 SAOHL3W TVOILATYNY 9 TON3HdJOHOTHOVIN3d 0914 TABLE 6-2. Analytical Methods for Determining Pentachlorophenol in Environmental Samples (continued) Sample matrix Egg Fish tissue Honey Preparation method Homogenize sample; extract with ethyl acetate-hexane; elute chlorophenol with methanol-chloroform Homogenize in water; acidify to pH 2 with HCI; extract with methylene chloride; extract with 0.1 N NaOH; acidify; extract with toluene, dry Dissolve sample in acidified water; extract onto Sep-Pak C,q cartridge; elute with hexane /diethyl ether Analytical method RPHPLC/UV GC/ECD GC/MS Sample detection limit <0.1 ppm 0.5 ppb 7.6 ng/kg Percent recovery 73-108% maximum 86% 84-102% Reference Mundy and Machin 1981 Kalman 1984 Muifio and Lozano 1991 CH4CN = acetonitrile; ECD = electron capture detector; FID = flame ionization detector; GC = gas chromatography; HCI = hydrochloric acid; HPLC = high performance liquid chromatography; H,SO,4 = sulfuric acid; MS = mass spectrometry; NaOH = sodium hydroxide; Na,SO, = sodium sulfate; RPHPLC = reverse phase high performance liquid chromatography; UV = ultra-violet detection SAOHLIW TVOILATYNY 9 JON3HJOHOTHOVIN3d L9t PENTACHLOROPHENOL 162 6. ANALYTICAL METHODS accurately detect pentachlorophenol at background concentrations in blood, urine, and adipose tissue. Only limited data exist on methods for metabolite characterization. TCHQ, tetrachloropyrocatechol, and palmitoyl-pentachlorophenol are the known metabolites of penta- chlorophenol. These compounds can be monitored using GC/ECD (Reigner et al. 1990) or mass spectroscopy (Edgerton et al. 1979). GC/ECD is cheaper than mass spectroscopy, but using GC/ECD for metabolite detection has been reported in only one study (Reigner et al. 1990). However, since the majority of pentachlorophenol is excreted unchanged, monitoring of metabolites might not provide useful additional information on exposure concentrations. In general, no attempts have been made to correlate levels of pentachlorophenol in the body with levels absorbed through skin or via inhalation. However, data from a study in log homes demonstrate a positive correlation between serum and urine concentrations of pentachlorophenol and indoor air concentrations of this compound (Hosenfeld et al. 1986). No identified biomarkers of effect (e.g., increased SGOT or SGPT enzyme levels in serum, increased blood urea nitrogen, or neurological symptoms) are specific for pentachlorophenol. The identification of specific biomarkers of effect may be useful. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Methods are available to measure pentachlorophenol in water, waste-water, effluent, sediment, and soil (Buisson et al. 1984; Butler and Dal Pont 1992; Carr et al. 1982; Cuiu et al. 1986; EPA 1986b; Ervin and McGinnis 1980; Giam et al. 1980; Hall et al. 1992; Lee et al. 1989; Morgade et al. 1980; Realini 1981; Rudling 1970; Wall and Stratton 1991: Xie 1983). Sensitivity is high and recovery is good. However, even though inhalation is considered to be a major route of human exposure, only limited data concerning methods for determining pentachlorophenol in air were located (Cuiu et al. 1986; Hall et al. 1992), and sensitivity or recovery data were not reported for these methods. Although both occupational exposure and exposure from sources such as log cabins are known to occur, methods for measuring ambient concentrations of pentachlorophenol in air are lacking. An additional source of pentachlorophenol exposure is food; methods are available for analyzing pentachlorophenol in animal tissue, eggs, and honey (Kalman 1984; Muifio and Lozano 1991; Mundy and Machin 1981). PENTACHLOROPHENOL 163 6. ANALYTICAL METHODS 6.3.2 On-going Studies L.L. Ingram, Jr., of the Forest Products Utilization Laboratory at Mississippi State University, is conducting research on the development of mass spectrometric methods for analysis of creosote and pentachlorophenol (CRISP 1992). The Environmental Health Laboratory Sciences Division of the National Center for Environmental Health and Injury Control, Centers for Disease Control, is developing methods for the analysis of pentachlorophenol and other phenolic compounds in urine. These methods use high resolution gas chromatography and magnetic sector mass spectrometry which gives detection limits in the low parts per trillion (ppt) range. PENTACHLOROPHENOL 165 7. REGULATIONS AND ADVISORIES The international, national, and state regulations and guidelines regarding pentachlorophenol in air, water, and other media are summarized in Table 7-1. ATSDR has derived an acute oral MRL of 0.005 mg/kg/day based on developmental effects observed in rats (Schwetz et al. 1974) and an intermediate oral MRL of 0.001 based on increased enzyme levels that may be indicative of hepatotoxicity (Knudsen et-al. 1974). EPA (IRIS 1993) assigned pentachlorophenol an oral reference dose (RfD) of 0.03 mg/kg/day with an uncertainty factor of 100 based on liver and kidney pathology in rats (Schwetz et al. 1978). EPA (IRIS 1993) has assigned pentachlorophenol a weight-of-evidence classification of B2, which indicates that it is a probable human carcinogen. Pentachlorophenol is on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of the Emergency Planning and Right-to-Know Act of 1986" (EPA 1988d, 1988e). EPA has restricted the sale and use of pesticide products containing pentachlorophenol (EPA 1987d). The International Agency for Research on Cancer (IARC) assigned pentachlorophenol a Group 2B classification, which means that it is possibly carcinogenic in humans. PENTACHLOROPHENOL 166 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Pentachlorophenol Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B2 IARC 1991 WHO Guideline for drinking water 10 pg/L WHO 1984 NATIONAL Regulations: a. Air: OSHA PEL TWA (skin) 0.5 mg/m3 OSHA 1989a (29 CFR 1910.1000): OSHA 1989b b. Water: EPA OWRS General pretreatment regulations for Yes EPA 1988f (40 CFR existing and new sources of 403, Appendix B); pollution EPA 1988g c. Food: FDA Listing as safe for use as a Yes FDA 1977a (21 CFR component of adhesives intended 175.105); FDA for use in packaging, transporting, 1977 or holding food d. Other: EPA OERR Reportable quantity 10 pounds EPA 1985 (40 CFR 302.4); EPA 1989a EPA OSW Designated as a hazardous substance Yes EPA 1985 (40 CFR 302.4); EPA 1989a Designated as a hazardous pollutant Yes EPA 1978b (40 CFR under section 311(b)(2)(A) of the 116.4); EPA 1978c Federal Water Pollution Control Act Designated as a toxic pollutant under Yes EPA 1979¢ (40 CFR Section 307(a)(1) of the Federal 401.15); EPA 1979d Water Pollution Act Groundwater monitoring requirement Yes EPA 1987c (40 CFR 264.94); EPA 1987f Land disposal restriction; treatment <1 ppb EPA 1991a (40 CFR standard 268); EPA 1991b Listing as a hazardous waste Discarded commercial chemical Yes EPA 1988a (40 CFR products, manufacturing inter- 261.33), EPA 1988b mediates, or an off-specification commercial chemical products Discarded unused formulations Yes EPA 1981a (40 CFR containing pentachlorophenol or 261.31); EPA 1981b compounds derived from penta- chlorophenol 167 PENTACHLOROPHENOL 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Pentachlorophenol (continued) Agency Description Information References STATE (Cont.) Connnecticut (8 hours) 1.00x10" ug/m3 Florida- Fort Lauderdale (8 hours) 5.001073 mg/m3 Florida-Pinellas (8 hours) 5.00 ug/m> Florida-Pinellas (24 hours) 1.20 ug/m3 Florida-Pinellas (Annual) 3.00x10! ug/m? Kansas (Annual) 2.56 pg/m Kansas- Kansas City (Annual) 2.56 ug/m> Massachusettes (24 hours) 1.00x10~2 ug/m> Massachusettes (Annual) 1.00x10°2 ug/m3 Maryland 0.00 Maine 0.00 North Carolina (1 hour) 2.50x10"2 mg/m> North Carolina (24 hours) 3.00x10°3 mg/m3 North Carolina- Forco (1 hour) 2.50x10"2 mg/m3 North Carolina- Forco (24 hours) 3.00x10"3 mg/m3 North Dakota (8 hours) 5.00x10"3 mg/m> Nevada (8 hours) 1.20x10"2 mg/m3 New York (1 year) 1.67 ug/m3 Oklahoma (24 hours) 5.00 ug/m3 Pennsylvania-Philadelphia (1 year) 1.20x10! ug/m> Pennsylvania-Philadelphia (Annual) 1.20x10" ug/m’ South Carolina (24 hours) 5.00 ug/m South Dakota (8 hours) 1.00x101 ug/m? Texas (30 minutes) 5.00 ug/m Texas (Annual) 500x107! pe/m’ Virginia (24 hours) 8.30 ug/m Vermont (Annual) 1.19 ug/m3 Kentucky Significant emission levels of toxic 1.276x107% NREPC 1986 air pollutants pounds /hour (401 KAR 63.022) b. Water: Drinking water quality guidelines FSTRAC 1988 Arizona 200 pg/L California 30 pg/L Kansas 220 ug/L Maine 6 ug/L Montana 220 pg/L PENTACHLOROPHENOL 168 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Pentachlorophenol (continued) Agency Description Information References STATE (Cont.) New York Drinking water quality criteria 21 pg/L CELDS 1992 Wisconsin Human threshold criteria WDNR 1987 Public water supply: Warm water sport fish communities 0.84 mg/L Cold water communities 0.76 mg/L Great Lakes communities 0.76 mg/L Non-water supply: Warm water sport fish communities 17 mg/L Cold water communities 5.4 mg/L Warm water forage and limited 180 mg/L forage fish communities and limited aquatic life c. Other: Restricted use of pesticide: special CELDS 1992 requirements on registration, permits, labeling, application, storage, disposal record keeping and/or reporting Alabama Alaska Arkansas Arizona California Colorado Connecticut Deleware Florida Georgia Hawaii Kansas Kentucky Illinois Iowa Maine Maryland Michigan Minnesota Missouri Montana Nevada New Hampshire New Jersey New Mexico North Carolina North Dakota Ohio Oklahoma Pennsylvania PENTACHLOROPHENOL 169 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Pentachlorophenol (continued) Agency Description Information References STATE (Cont.) South Carolina South Dakota Utah Vermont Virginia Washington Wyoming Effluent standards; hazardous waste CELDS 1992 discharge to water New York 21 pg/L Wisconsin 0.001 pg/L 8Group 2B: Possibly carcinogenic to humans PB2: Probable human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; ADI = Acceptable Daily Intake: EPA = Environmental Protection Agency; FDA = Food and Drug Administration; LARC = International Agency for Research on Cancer; NAS = National Academy of Science; ND = Not Determined; NIOSH = National Institute for Occupational Safety and Health; ODW = Office of Drinking Water; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; OTS = Office of Toxic Substances; OWRS = Office of Water Regulations and Standards; PEL = Permissable Exposure Limit: REL = Recommended Exposure Limit: RfD= Reicrence Dose; SNARL = Suggested No Adverse Response Level; TLV = Threshold Limit Value; TPQ = Threshold Planning Quantity; TWA = Time Weighted Average: WHO = World Health Organization PENTACHLOROPHENOL 171 8. 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Determination of trace amounts of chlorophenols and chloroguaiacols in sediment. Chemosphere 12:1183-1191. “Young HC, Carroll JC. 1951. The decomposition of pentachlorophenol when applied as a residual pre- emergence herbicide. Agron J 43:504-507. “Young HF, Lau L, Konno SK, et al. 1976. Water quality monitoring: Kaneohe Bay and selected watersheds July to December 1975 VL. Technical report No. 98. *Ziemson B, Angerer J, Lehnart G. 1987. Sister chromatid exchange and chromosomal breakage in PCP exposed workers. Int Arch Occup Environ Health 59:413-417. PENTACHLOROPHENOL 197 9. GLOSSARY Acute Exposure — Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K,) — The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) — The amount of a chemical adsorbed by a sediment or soil (i.c., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) — The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) — The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen — A chemical capable of inducing cancer. Ceiling Value — A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure — Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity — The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity — Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory — An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) — The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure — Exposure to a chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. PENTACHLOROPHENOL 198 9. GLOSSARY Immunologic Toxicity — The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro — Isolated from the living organism and artificially maintained, as in a test tube. In Vivo — Occurring within the living organism. Lethal Concentration; (,, (LCy¢) — The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration, (LCs) — A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose (LDy o) — The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose s0) (LDgg) — The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Times) (LTsy) — A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) — The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations — Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level — An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Mutagen — A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity — The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) — The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K,y) — The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. PENTACHLOROPHENOL 199 9. GLOSSARY Permissible Exposure Limit (PEL) — An allowable exposure level in workplace air averaged over an 8-hour shift. q,* — The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q,* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m> for air). Reference Dose (RfD) — An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) — The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity — The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) — The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity — This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen — A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) — A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) — An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDgy) — A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. PENTACHLOROPHENOL 200 9. GLOSSARY Uncertainty Factor (UF) — A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. PENTACHLOROPHENOL A-1 APPENDIX A USER’S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance. The major headings in the Public Health Statement are useful to find specific topics of concem. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and end point and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELSs), Lowest-Observed-Adverse-Effect Levels (LOAELS) for Less Serious and Serious health effects, or Cancer Effect Levels (CELSs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. (2). Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. PENTACHLOROPHENOL A-2 3). 4. (5). (6). ). (8). 9). (10). (11). (12). APPENDIX A Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELS can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table. Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELSs from different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated in this study. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "b"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. Reference The complete reference citation is given in Chapter 8 of the profile. CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses which did not cause a measurable increase in cancer. Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See LSE Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration. TABLE 2-1. Levels of significant Exposure to [Chemical x] - Inhalation Exposure Key to frequency/ figure* Species duration System NOAEL (ppm) LOAEL (effect) Less serious (ppm) Serious (ppm) Reference INTERMEDIATE EXPOSURE Systemic 18 13 wk Resp 5d/wk 6hr/d CHRONIC EXPOSURE Cancer 38 Rat 18 mo 5d/wk 7hr/d 39 Rat 89-104 wk 5d/wk 6hr/d 40 Mouse 79-103 wk 5d/wk 6hr/d ar 10 (hyperplasia) 20 (CEL, multiple organs) 10 (CEL, lung tumors, nasal tumors) 10 (CEL, lung tumors, hemangiosarcomas) Nitschke et al. 1981 Wong et al. 1982 NTP 1982 NTP 1982 * The number corresponds to entries in Figure 2-1. b> Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10” ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest -observed-adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk week (8) V XION3ddV JON3IHJOHOTHOVLIN3d ev FIGURE 2-1. Levels of Significant Exposure to [Chemical X] - Inhalation -——— 10-5 4 Estimated Upper- <=— Bound Human Cancer Risk INTERMEDIATE CHRONIC (15-364 Days) (> 365 Days) Systemic Systemic > id a oF & oF 5 & & & & : Ff <® ® ® Ff Ee FP ® <® (PPM) 10,000 1,000 - @1or @17 25m 100 @ D24¢ BD 3 Oz2ir P24g M21r O 220 ®:= Osem Paar Baar Baur Paar . 19r 38r 10 Ozm @rer @33m Oszr Poem BD Os Oser Os Ose Mare Saom Sse Q1arOter 1 1 1 1 I 0.1 : 10-4 1 0.01 1 1 I 0.001 1 ~ 10- 1 Levels 0.0001 Key io r Rat @ LOAEL for serious effects (animals) d } 0.00001 m Mouse ( LOAEL for less serious effects (animals) ) Minimal risk level for h Rabbit O NOAEL (animals) effects other than cancer g Guinea pig @ CEL - Cancer Effect Level (animals) ~r h Monkey The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 130017-1 V XION3ddV TTONIHdOHOTHOVLN3d vv PENTACHLOROPHENOL A-5 APPENDIX A (13). Exposure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14). Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. (15). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m’ or ppm and oral exposure is reported in mg/kg/day. (16). NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat). The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELSs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. (18). Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q;"). (19). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concemn to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. PENTACHLOROPHENOL A-6 APPENDIX A The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, -intermediate, - chronic). These MRLs are not meant to support regulatory action, but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible” provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by the Environmental Protection Agency (EPA) (Bames and Dourson 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all poten- tial effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELS for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continuous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when infor- mation from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor of (1, 3, or 10) is employed. MRLs are not derived from Serious LOAELSs. Additional uncertainty factors of (1, 3, or 10 ) are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and (1, 3, or 10) are used for inter- species variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. Generally an uncertainty factor of 10 is used; however, the MRL workgroup reserves the right to use uncertainty factors of (1, 3, or 10) based on scientific judgement. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. PENTACHLOROPHENOL B-1 ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F Fy FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd kg kkg Koc K ow APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECO Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient PENTACHLOROPHENOL L LC LC, LCs LD; LDs, LOAEL LSE m mg min mL mm mmHg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL Pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SMR APPENDIX B liter liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH’s Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio PENTACHLOROPHENOL STEL STORET TLV TSCA TRI TWA U.S. UF RR RIANA INV YV =e 8 APPENDIX B short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram Ww U.S. GOVERNMENT PRINTING OFFICE: 1994 — 5 3 7 -9 7 3 B-3 U. 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