Abstract  The potential for carcinogenic activity of three industrial solvents, trichloroethylene (79016) (TCE), perchloroethylene (127184) (PER), and pentachloroethane (76O17) (PENT), was investigated in mice and rats; the nephrotoxicity of the same substances was investigated in rats only. The animals were given TCE or PER at 1000mg/kg body weight or PENT at 150mg/kg body weight, in corn-oil by gavage for 10 days. The investigation was based on the hypothesis that the tumorigenicity of a substance is related to its enhancing effect on peroxisome proliferation. Peroxisome proliferation was determined by the palmitoyl-coenzyme-A (PCO) oxidation assay. The peroxisome proliferators, trichloroacetic-acid (TCA), a metabolite of TCE, and Wy-14,643, were used as standards. None of the three substances tested enhanced hepatic peroxisome proliferation in the rat. TCE and PER enhanced hepatic peroxisome proliferation in mice but not to the extent of the control substances, and PENT showed no enhancement of proliferation. All three substances caused increases in renal peroxisome activity in both rats and mice, with TCE inducing the greatest response. However, none of the test substances was as active as Wy-14,643. Nephrotoxicity was measured by induction of protein droplet nephropathy, postulated to be associated with abnormal alpha-2-mu-globulin activity in the epithelial cells of renal tubules. In male rats protein droplets and cell replication increased with PER or PENT administration. No effect was noted in male rats given TCE, or in female rats regardless of treatment. The authors conclude that there is a lack of a consistent relationship between the indicators of toxicity and carcinogenity of the three chemically related carcinogens tested

Abstract  The tumorigenicity of chloral hydrate (CH), trichloroacetic acid (TCA), trichloroethanol (TCE), malondialdehyde (MDA), crotonaldehyde, acrolein, and 4-hydroxy-2-nonenal (HNE) was tested in the B6C3F(1) neonatal mouse. Mice were administered i.p. injections of CH (1000, 2000, 2500, and 5000 nmol per animal), TCA (1000 and 2000 nmol), TCE (1000 and 2000 nmol), MDA (1500 and 3000 nmol), crotonaldehyde (1500 and 3000 nmol), acrolein (75 and 150 nmol), and HNE (750 and 1500 nmol) at 8 and 15 days of age. At 12 months, only male mice treated with the positive control chemicals, 4-aminobiphenyl (500 and 1000 nmol) and benzo[a]pyrene (150 and 300 nmol), had incidences of tumors in the liver significantly higher than the solvent control. Additional male mice were dosed as described above and their livers were excised at 24, 48 h, and 7 days after the final dose. Liver DNA was isolated and analyzed by 32P-postlabeling/high-performance liquid chromatography (HPLC) and HPLC/electrochemical detection for MDA-derived adduct (M(1)G) and 8-oxo-2'-deoxyguanosine (8-OHdG) formation, respectively. At 24 and 48 h after the final dose, CH- and TCA-treated mice exhibited significantly higher M(1)G levels than the controls. 8-OHdG formation was also induced by CH, TCA, and MDA. These results suggest that under these experimental conditions the B6C3F(1) neonatal mouse is not sensitive to carcinogens that induce an increase in endogenous DNA adduct formation through lipid peroxidation or oxidative stress.

Abstract  Trichloroethylene (TRI) (4–10 mmol/kg body wt) and tetrachloroethylene (PER) (4–8 mmol/kg body wt) were given to male mice by i.p. injection. The induction of single-strand breaks (SSB) in DNA of liver, kidney and lung was studied by the DNA unwinding technique. There was a linear increase of the level of SSB in kidney and liver DNA but not in lung DNA l h after administration. The damage was completely repaired 24 h after injection. The capability of TRI and PER to induce SSB in liver DNA is compared to that of three other substances, i.e., methyl methanesulfonate (MMS), styrene-7,8-oxide and styrene, which have been studied earlier by the same technique. The potency of the substances for induction of SSB was in the following order: MMS > styrene-7,8-oxide > styrene > PER > TRI.

Abstract  The mechanism of action of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16), an important antitumor agent, is unclear. There is evidence that DNA may be the target of action because VP-16 causes single-strand and double-strand breaks in DNA and produces cytotoxicity over a similar dose range. We have hypothesized that an enzyme system, such as dehydrogenase, catalyzes an oxidation-reduction reaction involving the pendant phenolic group which forms an active metabolite that causes the DNA damage and cytotoxicity. To test our hypothesis, we investigated the effect of disulfiram, an aldehyde dehydrogenase inhibitor, and its metabolite, diethyldithiocarbamate, on VP-16-induced DNA damage in L1210 cells. Using the alkaline elution technique to assay DNA damage, we found that disulfiram and diethyldithiocerbamate inhibited VP-16-induced single-strand breaks. Both compounds were also capable of significantly reducing VP-16-induced cytotoxicity. Oxalic acid, pyrophosphate, and malonic acid, competitive inhibitors of succinate dehydrogenase, and the naturally occurring dehydrogenase substrates, succinic acid, beta-glycerophosphate, and isocitric acid, also blocked the effects of VP-16. Free-radical scavengers were also studied. While sodium benzoate was particularly effective in preventing drug-induced DNA damage and cytotoxicity, a number of other scavengers were not. Our data are consistent with the hypothesis that VP-16 is activated by an enzyme such as a dehydrogenase which transforms it into an active intermediate resulting in DNA damage and, consequently, cell death.

Abstract  The 100-fold default uncertainty factor is used to convert a no-observed-adverse-effect level NOAEL) from a animal toxicity study, to a "safe" value for human intake. The composite uncertainty factor 100) has to allow for interspecies 10-fold) and interindividual 10-fold) differences in toxicokinetics and toxicodynamics. The aim of the current study was to assess the validity of the interspecies default for toxicokinetics 4.0) for each of the test species dog, rabbit, rat and mouse), using published data for compounds eliminated by CYP1A2 in humans caffeine, theobromine, theophylline and paraxanthine). An analysis of the published literature showed that the absorption, bioavailability and route of excretion were generally similar between humans and the test species, for each probe substrate. However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse 10.6) and rat 5.4) exceed the 4.0-fold default, whereas the rabbit 2.6) and dog 1.6) were below this value. This work supports the need to replace the generic default factors by a compound-related value derived from specific, relevant, quantitative data; this would result in more relevant and reliable non-cancer risk assessments.