7
Integration of Findings from the Toxicologic and Epidemiologic Literature

The charge to the committee was to review the scientific evidence concerning associations between exposure to contaminated water and adverse health effects applicable to the population at Camp Lejeune. To address the general evidence on health effects of trichloroethylene (TCE) and perchloroethylene (PCE), the committee reviewed the toxicologic literature (see Chapters 3 and 4) and the epidemiologic literature (see Chapters 5 and 6) for a comprehensive array of health outcomes, drawing on recent authoritative reviews where feasible and appropriate. This chapter considers those sets of literature together to identify health outcomes that are most plausibly due to TCE and PCE, focusing on health outcomes on which the lines of evidence converge.

In evaluating the potential for toxic effects in humans from a chemical exposure, data from human studies are usually considered the most relevant. However, human data are often limited by the size of the population(s) studied, the information on actual exposure concentrations, and other confounding factors. Thus, data from toxicologic studies are also used to evaluate the potential for various health effects from exposure to chemicals under more controlled conditions and usually at higher exposure concentrations than in the human population. The strength of the toxicologic data is dependent on the size, number, and types of studies conducted, as well as replication of study designs and results. The relevance of the animal data to humans is dependent on those factors as well as a number of toxicokinetic and dynamic factors, and they must be weighed carefully in evaluating the potential for environmental exposures to cause various health effects in humans.

In the following sections, the human and animal toxicologic data are discussed briefly for those health outcomes for which some information was available from both types of evidence. In some cases, the human data weighed more heavily because of the strength of the data and/or the association with the exposure. In other cases, the animal data weighed more heavily because of greater integrity of the data or more in-depth evaluation of the dose-response relationship and mechanisms involved.

CANCER OUTCOMES

Chapter 5 reviewed the epidemiologic studies and concluded that there was limited/suggestive evidence of an association between chronic exposure to TCE or PCE and cancers of the breast, bladder, kidneys, esophagus, and lungs. Toxicologic studies did not report significantly increased cancers of the breast, bladder, or esophagus, and rodent lung cancers were judged not to be relevant to humans because of known species differences in metabolism and organ sensitivity. Thus, for outcomes having limited/suggestive epidemiologic evidence of an association, positive concordance with the toxicologic evidence was strongest for kidney cancer. Studies of TCE and PCE found increases in kidney cancer in rats treated chronically at high doses. The mechanism by which the solvents exert their effects on the



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7 Integration of Findings from the Toxicologic and Epidemiologic Literature The charge to the committee was to review the scientific evidence concerning associations between exposure to contaminated water and adverse health effects applicable to the population at Camp Lejeune. To address the general evidence on health effects of trichloroethylene (TCE) and perchloro- ethylene (PCE), the committee reviewed the toxicologic literature (see Chapters 3 and 4) and the epidemiologic literature (see Chapters 5 and 6) for a comprehensive array of health outcomes, drawing on recent authoritative reviews where feasible and appropriate. This chapter considers those sets of literature together to identify health outcomes that are most plausibly due to TCE and PCE, focusing on health outcomes on which the lines of evidence converge. In evaluating the potential for toxic effects in humans from a chemical exposure, data from human studies are usually considered the most relevant. However, human data are often limited by the size of the population(s) studied, the information on actual exposure concentrations, and other confounding factors. Thus, data from toxicologic studies are also used to evaluate the potential for various health effects from exposure to chemicals under more controlled conditions and usually at higher exposure concentrations than in the human population. The strength of the toxicologic data is dependent on the size, number, and types of studies conducted, as well as replication of study designs and results. The relevance of the animal data to humans is dependent on those factors as well as a number of toxicokinetic and dynamic factors, and they must be weighed carefully in evaluating the potential for environmental exposures to cause various health effects in humans. In the following sections, the human and animal toxicologic data are discussed briefly for those health outcomes for which some information was available from both types of evidence. In some cases, the human data weighed more heavily because of the strength of the data and/or the association with the exposure. In other cases, the animal data weighed more heavily because of greater integrity of the data or more in-depth evaluation of the dose-response relationship and mechanisms involved. CANCER OUTCOMES Chapter 5 reviewed the epidemiologic studies and concluded that there was limited/suggestive evidence of an association between chronic exposure to TCE or PCE and cancers of the breast, bladder, kidneys, esophagus, and lungs. Toxicologic studies did not report significantly increased cancers of the breast, bladder, or esophagus, and rodent lung cancers were judged not to be relevant to humans because of known species differences in metabolism and organ sensitivity. Thus, for outcomes having lim- ited/suggestive epidemiologic evidence of an association, positive concordance with the toxicologic evidence was strongest for kidney cancer. Studies of TCE and PCE found increases in kidney cancer in rats treated chronically at high doses. The mechanism by which the solvents exert their effects on the 180

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Integration of Findings from the Toxicologic and Epidemiologic Literature 181 kidneys appears to be similar in rats and humans, and this strengthens the plausibility that these solvents caused kidney cancer in the occupational studies that found suggestive evidence of associations. Toxicologic studies have reported findings of liver cancer, lung cancer, male reproductive cancers, and mononuclear-cell leukemia in mice or rats exposed to high concentrations of TCE or PCE, but species differences in metabolism and response indicate that these cancers are not relevant to humans (see more detailed discussion in Chapter 4). The epidemiologic evidence on these cancers (except lung cancer) was judged to be inadequate/insufficient to determine whether associations exist. NONCANCER OUTCOMES Hepatic Toxicity Animal toxicity studies indicate that high concentrations of TCE and PCE are required to induce hepatocellular injury (cell replication, peroxisome proliferation, DNA adducts, and increase in serum enzymes released from damaged cells). Mice have a greater capacity to oxidize these solvents than humans. The epidemiologic evidence also shows clear effects of acute, high-level exposure to TCE and other solvents on the liver, but there is little evidence of persistent effects of chronic low-level exposure. The strongest evidence in the epidemiologic literature is limited/suggestive evidence of an association between chronic exposure to solvents and hepatic steatosis. Renal Toxicity TCE and PCE have some nephrotoxic potential in rodents and humans. Animal toxicity studies indicate that high concentrations of TCE and PCE are required to induce nephrotoxicity, such as injury to the proximal tubules, glomerulonephropathy, and karyomegaly. Chronic injury to cells of the proximal tubule is considered a prerequisite for the development of kidney cancer caused by TCE. The metabolism and mode of nephrotoxic action of TCE and PCE appear to be similar, although PCE and its metabolites appear to be more potent. Renal effects are due primarily to metabolites formed via the glutathione conjugation pathway. This metabolic pathway is similar qualitatively, but not quantitatively, in rats and humans. Humans have been shown to have a lower capacity than rats to convert TCE and PCE to reactive derivatives of glutathione conjugates. Epidemiologic studies of the effects of short-term and long-term solvent exposure on renal function have yielded limited/suggestive evidence of an association between high levels of solvent exposure, but not chronic low-level exposure, and acute tubular necrosis. A series of case-control studies of chronic glomerulonephritis in relation to solvent exposure have generated mixed evidence regarding an association; several reasonably strong positive studies showed dose- response gradients. Reproductive Outcomes The committee found independent toxicologic and epidemiologic evidence of associations between exposure to solvents and reproductive outcomes, but there was limited convergence for specific reproductive end points. For example, toxicologic studies have reported adverse effects on indicators of male fertility in rats and mice after high-dose exposure to TCE and PCE, respectively. Findings in human studies were not sufficiently consistent to support any firm conclusions, but a few studies showed a potential association with male infertility. With regard to female fertility, the epidemiologic evidence suggested an association between solvents in general and reduced fecundability (the ability to become pregnant), but there was little evidence in the toxicology literature to support female infertility, even after exposure at high concentrations.

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Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects 182 The human evidence of an association between chronic exposure to TCE or PCE and congenital malformations was judged to be inadequate to support conclusions. However, the toxicologic data provide strong evidence that neither solvent is associated with congenital malformations in rats. Adverse pregnancy outcomes (other than congenital malformations) were not seen in toxicologic studies of maternal exposure to TCE in rats, but reduced fetal weight in rats was seen in studies of maternal exposure to PCE. Data on female rats exposed before mating and during pregnancy indicate reduced offspring survival at high concentrations. Studies of mating pairs of rats or mice exposed during mating and throughout one or more pregnancies also showed reduced numbers of litters and increased perinatal mortality. Epidemiologic evidence provides some indication that solvent exposure during but not before pregnancy is associated with miscarriage but not with preterm birth or reduced birth weight, and there is no direct evidence on perinatal mortality. Although specific parallels between reduced litter size and perinatal mortality in rodent models and increased miscarriage in humans should not be drawn, the data suggest some corroboration of adverse reproductive effects of exposure during gestation. Pregnancy outcomes in rats after high maternal inhalation exposure to PCE indicate a reduction in intrauterine growth. Epidemiologic studies have addressed fetal growth after exposure to solvents in general and have not found sufficient evidence of an adverse effect. Only a few toxicologic studies of pregnancy outcomes after exposure of males before mating are available, and they indicate a reduction in number of litters at high inhalation concentrations. The epidemiologic evidence on paternal exposure to TCE and adverse pregnancy outcomes was inadequate/insufficient to support any conclusions. Neurologic Effects Epidemiologic studies of solvent exposure and neurobehavioral outcomes have for the most part addressed nonspecific solvents or solvents in the aggregate. Overall, there is limited/suggestive evidence of an association between principally inhalation exposure to solvents and neurobehavioral outcomes; the most support is of visuomotor and motor function, fatigue, headache, and deficits in concentration. Most of those effects were reported concurrently with exposure, and there has been little study of whether effects persist after exposure ceases. Animal toxicologic studies also report effects on the nervous system, such as depression of the central nervous system, attention deficits, deficits in visual discrimination, alterations in visual evoked potentials, altered sleep pattern, and reduced exploratory behavior in rats and rabbits exposed for weeks to moderate vapor concentrations of TCE. These changes generally appear to be reversible. Residual auditory loss resulting from losses of cochlear spiral ganglion and hair cells have been observed in rats inhaling high concentrations of TCE. Similar effects have been found in rodents exposed to PCE. In addition, studies of PCE have shown changes in behavior and neurochemical markers at lower levels. Some animal data suggest sensitive windows during development when organisms are more susceptible to PCE exposure, which results in alterations of neurologic development and behavior. Immunologic Outcomes Epidemiologic studies have provided some support of two immunologically mediated end points: chronic glomerulonephritis and scleroderma. There is limited/suggestive evidence of an association between mixed solvent exposure and both end points and some indication of a specific association between TCE and scleroderma. The toxicologic data provide strong evidence that TCE can act as a skin sensitizer, modulate existing asthma, produce immunosuppression, and influence autoimmune diseases. Data on PCE have only a suggestion of effects on allergic sensitization and immunosuppression.

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Integration of Findings from the Toxicologic and Epidemiologic Literature 183 CONCLUSIONS The committee did not find sufficient evidence to justify causal inference for any health effects it reviewed. However, some effects were identified from a review of the collective evidence from epidemiologic and toxicologic investigations as being relevant health outcomes to consider in future studies of exposures at Camp Lejeune, including kidney cancer, renal toxicity, hepatic toxicity, neurotoxicity, and autoimmune disease. Although other health end points with less support from the existing literature should not be excluded from consideration, such findings are more likely to reflect random error if not supported by additional contexts in the literature.