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Pesticides and other agricultural chemicals are now widely used throughout the world as a means of improving crop yields in order to meet the increasing demands being placed upon the global food supply. In Canada, the use of such chemicals is controlled through government regulations established jointly by the Department of Agriculture and the Department of National Health & Welfare. Such regulations require a detailed evaluation of the toxicological characteristics of the chemical prior to its being cleared for use. In this paper, procedures for assessing the carcinogenic potential of agricultural and other chemicals are discussed. Consideration is given to both the classical long-term in vivo carcinogen bioassay in rodent or other species and the more recently developed short-term in vitro tests based on genetic alterations in bacterial and other test systems.

Although procedures for assessing the carcinogenic risks associated with exposure to individual chemicals are relatively well developed, risk assessment methods for mixtures of chemicals are still in the developmental stage. In this paper, we examine the difficulties in assessing the risks of exposure to complex mixtures, with special reference to the potential for synergistic effects among the components of the mixture. Statistical models for describing the joint action of multiple exposures are reviewed, and their implications for low-dose risk assessment are examined. The potential use of pharmacokinetic models to describe the metabolism of mixtures is also considered. Application of these results in regulating mixtures of carcinogenic substances is illustrated using examples involving multiple contaminants in drinking water and polycyclic aromatic hydrocarbons produced from combustion sources.

The association between selected neuropathological lesions and effects on mitochondrial and nuclear DNA synthesis was explored in cats exposed in vivo to methylmercuric chloride. Two groups of eight adult female cats ingested 0 or 176 micrograms Hg/kg body wt/day as methylmercuric chloride added daily to their diet. Treated animals and concurrent controls were sacrificed following the onset of clinical signs of toxicity, with the mean termination time being about 12 (range 7-15) weeks. Terminal Hg levels for the control and treated groups respectively were 0.16 +/- 0.02 and 12 +/- 1 ppm in the cerebrum and 0.16 +/- 0.01 and 14 +/- 1 ppm in blood. Hydroxyurea-resistant [3H]thymidine incorporation into DNA in cultured explants of cerebrum and cerebellum, as measured by scintillation counting of extracted DNA, was elevated for treated animals. Autoradiographic analysis indicated that the excess DNA synthesis was cytoplasmic, and deoxyribonuclease resistant, suggesting a mitochondrial DNA origin. The excess DNA synthesis was pronounced in cell types prone to neurodegeneration, specifically the Purkinje cells and the granular cell layer in the cerebellum and the large neurons in the cerebrum. Mitochondrial DNA from neural tissues of an additional five pairs of cats treated for 8 weeks was isolated from cesium chloride/ethidium bromide density gradients. Thymidine incorporation into mitochondrial DNA was greater in methylmercury-treated than control animals. These observations indicate that methylmercury affects mitochondrial DNA synthesis in vivo with a tissue specificity parallel to that of neuropathological lesions.

The assessment of health risks due to low levels of exposure to potential environmental hazards based on the results of toxicological experiments necessarily involves extrapolation of results obtained at relatively high doses to the low dose region of interest. In this paper, different statistical extrapolation procedures which take into account both time-to-response and the presence of competing risks are compared using a large simulated data base. The study was designed to cover a range of plausible dose response models as well as to assess the effects of competing risks, background response, latency and experimental design on the performance of the different extrapolation procedures. It was found that point estimates of risk in the low dose region may differ from the actual risk by a factor of 1000 or more in certain situations, even when precise information on the time of occurrence of the particular lesion of interest is available. Although linearized upper confidence limits on risk can be highly conservative when the underlying dose response curve is sublinear in the low dose region, they were found not to exceed the actual risk in the low dose region by more than a factor of 10 in those cases where the underlying dose response curve was linear at low doses.

The process of environmental health risk assessment may be described as a series of distinct stages, ranging from hazard identification and risk estimation to the selection and implementation of an appropriate risk management strategy. An important step in this process is the estimation of health risks at low levels of exposure. The toxicological and epidemiological data base on which such estimates are based are reviewed in the case of hexachlorobenzene (HCB), a persistent organochlorine pesticide, along with data on human exposure. This information is used to assess the potential human health risks attributable to HCB.

A case-control study was undertaken in Montreal to investigate the possible associations between occupational exposures and cancers of the following sites: oesophagus, stomach, colo-rectum, liver, pancreas, lung, prostate, bladder, kidney, melanoma and lymphoid tissue. In total, 3,726 cancer patients and 533 population controls were interviewed to obtain detailed lifetime job histories and information on potential confounders. Each job history was translated into a history of occupational exposures. Because of current concerns about formaldehyde carcinogenicity, we carried out a special analysis of the association between exposure to formaldehyde and each type of cancer covered by this study. Separate statistical analyses were carried out for each type of cancer using population controls as well as a control series drawn from among the other cancer sites in the study. Although nearly a quarter of all subjects had undergone occupational exposure to formaldehyde, the levels of exposure were in general quite low. There was no persuasive evidence of an increased risk of any type of cancer among men exposed to these levels of formaldehyde. However, the possibility of a small increase in risk could not be ruled out.

The object of regulatory toxicology is to determine "safe" levels of human exposure to toxicants present in the environment. The traditional safety factor approach is compared to more recent mathematical modeling techniques, outlining the underlying assumptions and statistical properties of each procedure. Several linear extrapolation procedures are examined in detail using computer simulation, along with the impact of nonlinear kinetics on the extrapolation process.

Following a number of recent reports on the presence of mutagens in certain foods, a general survey of the mutagenic potential of a wide variety of food products has been initiated. Here, results for samples of 28 widely consumed beverages from 13 general categories are reported. Each sample was concentrated and fractionated by polarity and solubility to give up to seven fractions, each of which was assayed for mutagenic potential with Salmonella typhimurium TA98 and TA100 +/- fortified liver homogenate. Fractions showing evidence of either mutagenicity or toxicity were retested at the same and lower concentrations. The utility of the fractionation procedure and the sensitivity of the screening strategy were established by assaying six beverages spiked with known mutagens prior to fractionation. Statistical analysis of the data resulted in positive findings for seven beverages, although confirmation of these results through analysis of a second sample was obtained only for red wine, grape juice, and instant coffee. The remaining 21 beverages showed no strong evidence of mutagenic activity. For those foods for which the variation among replicate plates was largest, the false-positive rate for the two-stage screening procedure employed was estimated to be less than 1% while the false-negative rate for a beverage inducing a threefold increase in the background mutation rate was conservatively estimated to be limited to 14%.