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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