Toxicokinetic data

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective on the toxicology of methyl parathion. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

Fazekas 1971) exposed by various routes. Because of a lack of toxicokinetic data, it cannot be assumed that the end points of methyl parathion toxicity would be quantitatively similar across all routes of exposure. The acute effects of dermal exposures to methyl parathion are not well characterized in humans or animals. Therefore, additional dermal studies are needed. 

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

A 52-week study in monkeys was designed to evaluate ocular effects. Despite the absence of adverse toxicological effects at the highest dose tested (20 mg/kg body weight per day), the study was considered inappropriate for the establishment of an ADI in view of the much higher doses used in several other studies and found to be without effects. The available comparative toxicokinetic data for humans and rats indicated that studies of toxicity in rats could be used to derive an ADI. 

No studies were located regarding toxicokinetic data in humans. Limited information is available regarding the toxicokinetic differences among animal species. Rats, mice, mink, and dogs showed rapid absorption, wide distribution, and over 90% urinary excretion of diisopropyl methylphosphonate or its metabolites. However, the rates of absorption and patterns of distribution varied (Hart 1976 Weiss et al. 1994). The mechanism of toxicity is also undetermined. From the limited data available, it is not possible to determine the degree of correlation between humans and animals. 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Comparative Toxicokinetics. The toxicokinetic studies available indicate that the rat is a good model for human neurotoxicity observed after occupational exposure to 77-hexane. Mild signs can be produced in chickens and mice, but these do not progress to the serious neurotoxicity observed in humans and rats. Toxicokinetic data from other species (absorption, distribution, metabolism, excretion) could provide insight on the molecular mechanism(s) of the species specificity of 77-hexane toxicity and would be valuable for predicting toxic effects in humans. 

The lipophilic properties of disulfoton suggest that the compound is likely to be absorbed readily by the lungs, gastrointestinal tract, and the skin. Toxicokinetic data in humans and animals show that disulfoton is readily and extensively absorbed by the gastrointestinal tract. Disulfoton and/or its... 

With intraperitoneal administration, rats eliminated 28% of the original dose within 48 hours (Bull 1965), and mice eliminated 30 60% of the original dose within 96 hours (March et al. 1957). There appears to be insufficient toxicokinetic data to use as a basis for comparison of animals and humans. Additional studies comparing the rate and extent of absorption, distribution, and elimination in several different animal species after inhalation, oral, and dermal exposure to disulfoton could be useful. 

Comparative Toxicokinetics. Available studies indicate that bromomethane affects the same target tissues in humans and animals, although there are apparent differences in sensitivity between species, with rabbits being more sensitive than rats or mice (Irish et al. 1940). However, quantitative toxicokinetic data on absorption, distribution, and excretion are available only for rats (Bond et al. 1985 Gargas and Andersen 1982 Honma et al. 1985 Jaskot et al. 1988 Medinsky et al. 1984, 1985). Additional toxicokinetic studies would be helpful in understanding the basis of the... 

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

The dermal LD50 for 1,4-dichlorobenzene in Sherman rats was greater than 6,000 mg/kg/day (Gaines and Linder 1986). It is not clear how many rats died after dermal exposure to 1,4-dichlorobenzene in this study, and there are no toxicokinetic data that address the question of absorption of 1,4-dichlorobenzene by the dermal route. 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

A recently pubhshed WHO/IPCS document regarding chemical-specific adjustment factors for interspecies differences and human variability (WHO/IPCS 2005) provides guidance for use of toxicokinetic data in dose-response assessment to develop the so-called Compound-Specific Assessment Factors (CSAFs) (Section 5.2.1.12). 

Toxicokinetic data can also be used to make informed decisions on testing of chemical substances. In specific circumstances, valid toxicokinetic data may be used to support a decision to omit testing for systemic effects, e.g., in cases where the toxicokinetic data provide sufficient evidence that a substance is not absorbed and therefore not systemically available, i.e., no plasma/blood concentrations were measurable and no parent compound or metabolites could be detected in urine, bile, or exhaled air. For example, in vivo testing for mutagenicity, reproductive toxicity, or carcinogenicity may be omitted if toxicokinetic data or other data indicate a lack of systemic availability. 

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