Contaminated Water Supplies at Camp Lejeune Assessing Potential Health Effects (2009) / Chapter Skim
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4 Review of Toxicologic Studies
4 Review of Toxicologic Studies
Pages 90-133
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From page 90... ...
At the conclusion of this toxicologic review, a hazard evaluation of TCE and PCE exposure at Camp Lejeune was conducted for selected health end points. A hazard evaluation is conducted to provide information on the intrinsic toxic potential of an exposure and is not meant to provide a quantitative risk assessment.
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From page 91... ...
; the researchers proposed that trichloroacetic acid and dichloroacetic acid cause peroxisome proliferation and the ensuing generation of reactive moieties that deplete glutathione and can cause oxidative injury. Dichloroacetic acid does not induce peroxisome proliferation in male B6C3F1 mice in the same dose range at which it produces hepatic tumors (DeAngelo et al.
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From page 92... ...
It is thought that humans, like rats, have lower rates of oxidative metabolism and higher rates of conjugation than do mice. Trichloroacetic acid produces hepatic tumors only in B6C3F1 mice, but dichloroacetic acid induces them in mice and in F344 rats at exposures up to 5 g/L in drinking water for 104 weeks (HerrenFreund et al.
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From page 93... ...
Thus, the authors concluded that there was no persuasive evidence of a causal relationship between choral hydrate exposure and cancer in humans, but they were unable to rule out a causal relationship because statistical power was low. Trichloroacetic acid elicits hepatic tumors in mice with a phenotype typical of peroxisome proliferators, whereas dichloroacetic acid produces hepatic tumors with a distinctly different phenotype and also increases tumor growth (Bull 2000; Thai et al.
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From page 94... ...
Very high concentrations of dichloroacetic acid and chloral hydrate have a weak genotoxic action in vitro.
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From page 95... ...
Necrosis, however, was a late, high-dose phenomenon in this cell system. Exposure of human renal proximal tubular cells to DCVC at lower concentrations for 10 days also resulted in expression of genes associated with cell proliferation, apoptosis, and stress (Lash et al.
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From page 96... ...
Environmental Protection Agency with pooling across strains indicated a modest tumor effect in female rats (EPA 2001)
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From page 97... ...
Taken together, results in the cited studies indicate that male humans and male rats both possess significant glutathione conjugation capacity and can produce the critical TCE metabolite DCVC; renal carcinoma has been observed in male rats and male workers when both have been exposed to high TCE concentrations for prolonged periods of time. These observations show data congruence, indicating that the conjugation pathway plays a central role in induction of renal carcinoma in males of both species.
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From page 98... ...
TCE oxidative metabolites trichloroacetic acid, dichloroacetic acid, and chloral hydrate generally have shown weak or no reactivity in mutagenicity tests; the weight of evidence in both in vitro and in vivo test sys
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From page 99... ...
. Gene expression controlling cell growth, tissue remodeling, and xenobiotic metabolism was altered in in dichloroacetic acid-induced mouse hepatic tumors (Thai et al.
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From page 100... ...
Female rats were exposed to several male reproductive toxicants, including TCE, at 0.45% in drinking water for 2 weeks (Berger and Horner 2003)
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From page 101... ...
The NOAEL was about 70 mg/kg per day in rats and 405 mg/kg per day in mice. Additional studies of the reproductive toxicity of TCE are needed to permit better identification of LOAELs and NOAELs in both male and female rats and mice.
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From page 102... ...
. In most cases, the TCE metabolites trichloroacetic acid and dichloroacetic acid were also studied and found to be at least as effective as TCE.
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From page 103... ...
(2006) reported immunotoxicity after developmental exposure of mice to TCE at 0, 1,400, or 14,000 ppb in drinking water from gestational day 0 through the age of 3 weeks or 8 weeks.
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From page 104... ...
Inhalant abuse is the extreme form of TCE exposure, in that participants repeatedly subject themselves to vapor concentrations high enough to produce narcosis. Occupational exposures to TCE often involve inhalation of relatively high concentrations for years.
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From page 105... ...
. Reduced exploratory and social behavior was seen in rats after weeks of daily 6- to 7-h exposures to TCE vapor concentrations as low as 100 ppm.
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From page 106... ...
Those activity increases reflect the initial stimulant phase of action of CNS depressants. A few studies of TCE exposure in drinking water at about 30 mg/kg per day during pregnancy and lactation reported increased activity, reduced 2-deoxyglucose uptake in brain, and reduced hippocampal myelin (Taylor et al.
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From page 107... ...
(2006) recently reported that mice exposed prenatally and postnatally to TCE are immunosuppressed at concentrations as low as 1.4 ppm in drinking water from gestation day 0 through the age of 3 or 8 weeks.
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From page 108... ...
. The California Environmental Protection Agency published a public-health goal for PCE in drinking water (CalEPA 2001)
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From page 109... ...
(1986) found no consistent dose-related effects on any hematologic or clinical-chemistry measure in male or female rats that ingested PCE at about 14, 400, or 1,440 mg/kg per day for 90 days.
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From page 110... ...
. Inhalation exposure of 50 B6C3F1 mice of each sex at 0, 100, and 200 ppm 6 h/day 5 days/week for 103 weeks caused increased incidence of hepatocellular neoplasms (adenomas and carcinomas combined)
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From page 111... ...
TABLE 4-2 Animal Cancer Studies of PCE Determined to be Negative, Inadequate, or Incomplete Species Strain Dose or Concentration Route Timing and Duration Outcomes Comment NOAEL Reference Rat Osborne Males, 471, 941 mg/kg Oral gavage 78 weeks Early mortality due to Inadequate -- NCI 1977 Mendel per day; females, (corn oil) PCE-induced toxic study 474, 949 mg/kg per day nephropathy Rat Sprague- 0, 300, 600 ppm, Inhalation 52 weeks, then held Hematologic examinations Short duration 600 ppm Rampy et al.
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From page 112... ...
Dose-dependent karyomegaly was observed in each sex of rats exposed to PCE at 200 or 400 ppm and mice exposed at 100 and 200 ppm chronically (NTP 1986a) ; there were also low incidences of renal proximal tubular-cell hyperplasia in the male rats.
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From page 113... ...
Pulmonary congestion was seen in mice that inhaled PCE at 100 ppm or greater in the 103-week phase of the cancer bioassay. There was not an increased incidence of lung tumors in the mice or rats.
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From page 114... ...
involved exposure of male and female rats (Alpk:ApfSD) to PCE at 0, 100, 300, or 1,000 ppm 6 h/day 5 days/week for 11 weeks before mating and then daily during mating and through gestation to day 20.
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From page 115... ...
(1982) studied the effects of PCE exposure at 1,000 ppm in Long-Evans female rats before mating and during pregnancy or only during pregnancy to determine the more sensitive window.
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From page 116... ...
(1991) reported EEG changes and decreased latency of flash-evoked potentials and somatosensory evoked potentials in male rats exposed to PCE at 800 ppm 4 h/day for 4 days.
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From page 117... ...
(1984) reported increased plasma butyrylcholinesterase concentrations and reduced body weight in white male and female MRI mice exposed to PCE at 37 ppm or greater for 30 days.
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From page 118... ...
Exposure of young rats (45-50 g) to PCE at 5 or 50 mg/kg per day 5 days/week for 8 weeks resulted in effects on pain threshold, locomotor activity, and seizure susceptibility; changes in locomotion at the high dose; and reduced body-weight gain at 5 and 50 mg/kg (Chen et al.
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From page 119... ...
Nonetheless, there remain potential health effects of exposure to TCE and PCE on which there are inconclusive data or no data at all. The committee used a number of criteria in assessing the evidence in human case reports
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From page 120... ...
Later in this chapter, LOAELs for selected end points are compared with estimated ranges of TCE and PCE doses by simultaneous ingestion and inhalation experienced by former residents of Camp Lejeune from exposure to contaminated water supplies. Trichloroethylene Hepatic Effects Toxicity TCE, even in very high oral doses, has little ability to damage the livers of rodents or humans.
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From page 121... ...
Centrilobular necrosis, bile stasis, hepatocellular proliferation in mice (NTP 1986a) Kidney tubular cell adenomas and adenocarcinomas in male ratsa (NTP 1986a)
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From page 122... ...
1982) aGeneral toxicity -- for example, reduced body weight, weight gain, or food consumption -- that may influence effects were observed in the study.
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From page 123... ...
LOAELs of 250 and 500 mg/kg for proximal tubular-cell proliferation and karyomegaly, respectively, have been reported. Those responses were observed in male rats exposed orally five times a week for 13 weeks.
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From page 124... ...
The male rats ingested TCE at estimated doses of 1.6-3.7 mg/kg per day in drinking water for 14 days. Replication of those findings and further studies of the toxicologic and human significance of that sperm effect are warranted.
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From page 125... ...
Karyomegaly was seen in the renal tubular cells of mice and rats that inhaled PCE chronically at as low as 100 and 200 ppm, respectively; the nuclear enlargement may be a predecessor of neoplasia, but a definite link has not been established. Renal effects of PCE are due primarily to metabolites formed via the glutathione conjugation pathway.
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From page 126... ...
Renal tumors did not occur in female rats or in mice of either sex, although these animals did exhibit karyomegaly. Pulmonary Effects Toxicity There is little evidence of lung injury by inhaled PCE in laboratory animals or humans.
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From page 127... ...
Further investigations of PCE are warranted in light of the apparent effects of TCE on the immune system. HAZARD EVALUATION OF TRICHLOROETHYLENE AND PERCHLOROETHYLENE EXPOSURE FOR SELECTED END POINTS The committee used several approaches to consider the health significance of the solvents found in the water supply at Camp Lejeune.
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From page 128... ...
The intent is to provide general comparisons of the lowest doses at which specific adverse health effects were observed in experimental toxicologic studies with a range of estimated contaminant concentrations that may have occurred in the Camp Lejeune water supply. The following describes the assumptions in the evaluation and illustrative calculations.
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From page 129... ...
. Given the sparse information regarding the range and magnitude of contaminant concentrations in the Camp Lejeune water supply, values that correspond to half the highest measured value, the highest measured value, and twice the highest measured value were selected for this exercise: TCE at 700, 1,400, and 2,800 µg/L and PCE at 100, 200, and 400 µg/L.
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From page 130... ...
. The estimated human adult dose at Camp Lejeune is 550 times lower than the LOAEL for exposure at half the highest water-supply concentration, 275 times lower than the LOAEL for exposure at the highest concentration, and 110 times lower than the LOAEL for exposure at twice the highest concentration.
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From page 131... ...
The dose comparisons1 suggest considerable differences between the estimated doses from human exposure to contaminated water supplies at Camp Lejeune under conservative assumptions of exposure and the lowest doses associated with the development of renal toxicity, kidney cancer, neurotoxicity, and immunosuppression in rodents. The drinkingwater doses at Camp Lejeune are substantially lower.
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From page 132... ...
CONCLUSIONS TCE and PCE are well-studied compounds compared with most other compounds of environmental concern. On the basis of the review presented above, the committee concludes that the strongest evidence of health effects of relevance to humans are renal toxicity, kidney cancer, neurobehavioral effects, and immunologic effects, which have generally been observed at high concentrations in a workplace setting and in exposure to tens to thousands of milligrams per kilogram of body weight in animal studies.
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From page 133... ...
Observations in animal studies indicate that very high acute or chronic doses of TCE or PCE are necessary to injure renal proximal tubular cells. Results of occupational-exposure studies indicate that relatively high, chronic exposures result in modest, reversible changes in the most sensitive indexes of renal injury in workers.
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