Toxicokinetics dermal

Walsh, C.T. 1990. Anatomical, Physiological, Biochemical Characteristics of the Gastrointestinal Tract. Iln T.R. Gerrity and C.J. Henry, Eds., Principles of Route-to-Route Extrapolation for Risk Assessment, pp 33-50. Elsevier New York, N.Y.Wester, R.C., and H.I. Maibach. 1997. Toxicokinetics Dermal Exposure and Absorption of Toxicants. In I.G. Sipes, C.A. McQueen, and A.J. Gandolfi, Eds., Comprehensive Toxicology Volume General Principles (J. Bond, volume editor), pp. 99-114. Pergamon Press, New York, N.Y. 

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. 

Absorption, Distribution, Metabolism, and Excretion. Evidence of absorption comes from the occurrence of toxic effects following exposure to methyl parathion by all three routes (Fazekas 1971 Miyamoto et al. 1963b Nemec et al. 1968 Skiimer and Kilgore 1982b). These data indicate that the compound is absorbed by both humans and animals. No information is available to assess the relative rates and extent of absorption following inhalation and dermal exposure in humans or inhalation in animals. A dermal study in rats indicates that methyl parathion is rapidly absorbed through the skin (Abu-Qare et al. 2000). Additional data further indicate that methyl parathion is absorbed extensively and rapidly in humans and animals via oral and dermal routes of exposure (Braeckman et al. 1983 Flollingworth et al. 1967 Ware et al. 1973). However, additional toxicokinetic studies are needed to elucidate or further examine the efficiency and kinetics of absorption by all three exposure routes. 

A study of the dermal toxicokinetics of methyl parathion in female rats, sponsored by ATSDR, is being conducted at the University of Mississippi Medical Center. The principal investigator is Dr. Ing K. Ho, Department of Pharmacology and Toxicology, 500 North State Street, Jackson, Mississippi 39216-4505. 

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. 

Absorption, Distribution, Metabolism, and Excretion. Metabolism and excretion in animals exposed to acrylonitrile by the inhalation and oral routes have been studied extensively. However, only limited data on absorption and distribution are available. Some data on humans exposed by inhalation are available. No data are available on the toxicokinetics of acrylonitrile when the exposure route is dermal. More extensive information on absorption and distribution of acrylonitrile would be valuable to fully understand the toxicokinetics of acrylonitrile. Some data on the toxicokinetics of acrylonitrile... 

The application of toxicokinetic modeling to the assessment of interactive effects between hexane, ketones and aromatic compounds. Investigation of dermal absorption of polycyclic aromatic compounds (PAHs). Research indicates dermal absorption of PAHs in a number of industries including aluminum smelting, coke ovens, creosote production and others is significantly more important than previously recognized. 

To date, very little quantitative data exist regarding the toxicokinetics of endrin and its metabolites. Limited data were found regarding the absorption, distribution, metabolism, and excretion of endrin in humans and animals after inhalation, oral, or dermal exposure, which is especially relevant to occupational exposure scenarios. Endrin appears to be well absorbed orally, and distribution is primarily to fat and skin. Endrin is excreted in urine and feces, and the major biotransformation product is anti-12-hydroxy-... 

No studies were located regarding the toxicokinetics of di-/ -octylphthalate in humans or animals following inhalation or dermal exposure. Information on the toxicokinetics of 6i-n-octylphthalate in humans following oral exposure is not available. There are studies that provide indirect evidence for the oral absorption of di- -octylphthalate in animals (Albro and Moore 1974 Oishi 1990 Poon et al. 1995) however, quantitative information is lacking on the rate and extent of absorption following oral exposure to di- -octylphthalate. Information on the distribution of di-w-octylphthalate is limited to oral studies in rats by Oishi (1990), which reported the identification of mono- -octy lphthalate in blood and testes within 1-24 hours (plasma peak at 3 hours, testes peak at 6 hours) after dosing, and by Poon et al. (1995), which reported di- -octylphthalate... 

The toxicokinetics of disulfoton in humans and animals depends on its physicochemical characteristics and its metabolism. The lipophilicity of disulfoton indicates that the insecticide should be easily absorbed by oral, inhalation, and dermal routes. No bioavailability data were located for inhalation and dermal exposure. However, disulfoton is almost completely absorbed from the gastrointestinal tract within 2 days after oral exposure. Animal studies suggest that disulfoton is widely distributed primarily to the liver and in smaller quantities to the kidney, fat, skin, muscle, brain, and other organs. Disulfoton and/or its metabolites are excreted mainly in the urine of humans and animals, with minor amounts excreted in the feces and expired air. 

Evidence further suggests that male rats eliminate disulfoton at a faster rate than females. This difference may be due to differences in absorption, metabolism, retention, excretion, or a combination of factors. The metabolic pathways of disulfoton are relatively well understood based on data from animal studies (Bull 1965 Lee et al. 1985 March et al. 1957 Puhl and Fredrickson 1975). Similar metabolites have been detected in the urine and tissues from humans exposed to disulfoton (Brokopp et al. 1981 Yashiki et al. 1990). One study suggests that a greater percentage of disulfoton sulfoxide is oxidized to demeton S-sulfoxide, rather than disulfoton sulfone to form demeton S-sulfone (Bull 1965). Additional studies in animals, designed to measure the rate and extent of absorption, distribution, and excretion of disulfoton after inhalation or dermal exposure would be useful for predicting the toxicokinetics of disulfoton in humans at an occupational or hazardous waste site. 

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. 

Bioavailability from Environmental Media. Available information regarding the rate of disulfoton absorption following inhalation, oral, or dermal contact has been discussed in the Toxicokinetics section (see Section 2.3). Although no data on disulfoton s bioavailability from contaminated air are available, the bioavailability from inhalation exposure is expected to be high because disulfoton is likely to be present in the vapor phase (Eisenreich et al. 1981) and not in the particulate phase in the adsorbed state. Similarly, no data on the bioavailability of disulfoton from water and soil or plant material are available however, disulfoton adsorbs rather strongly to soil (Harris 1969 Helling et al. 1974 Wauchope et al. 1992). Since the part that remains adsorbed to soil or sediments may, at most, be partially bioavailable, disulfoton is expected to have reduced bioavailability from soil and water. Data on the bioavailability of disulfoton from actual environmental media need further development. 

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. 

Studies using the dermal route for intermediate-duration exposure would be useful if absorption and systemic distribution of 1,4-dichlorobenzene by this route could first be demonstrated in toxicokinetic studies. In any further studies conducted for this duration period, methemoglobinemia, neurological effects, and effects on sperm morphology would be valuable. 

Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1,4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. 

Animal data include an inhalation study in rabbits that resulted in an increased incidence of retroesophageal right subclavian artery in the fetuses (Hayes et al. 1985), and an oral study in rats that resulted in an increased incidence of an extra rib (NTP 1987). The data were considered sufficient to derive an acute-duration inhalation MRL of 0.8 ppm, based on a NOAEL of 300 ppm for lack of developmental effects in rabbits. It would be useful to have additional information on the developmental effects of 1,4-dichlorobenzene by inhalation and oral exposure in relation to maternal toxicity. There are currently no data available for the dermal route. Information on the developmental effects of dermal exposures would be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene could be demonstrated in toxicokinetic studies. 

Distribution, including accumulation of an absorbed substance, will be the same irrespective of the route of administration. However, distribution and accumulation at the site of apphcation (inhalation, oral, dermal) may depend on the route of administration. In such cases, local accumulation may occur and may be responsible for tissue damage. In these cases, systemic toxicokinetics of the substance may be of limited relevance for the risk assessment. It is generally not cmcial for risk assessment to determine the precise tissue distribution profile for a substance. In certain special cases, however, specific tissue distribution studies may assist or even be essential for the interpretation of available toxicological data. For example, it may be of interest to know whether the substance will cross the blood-brain barrier, the placenta barrier, or will accumulate in specific tissues. 

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