Toxicokinetics in humans

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Comparative Toxicokinetics. No studies were located in which toxicokinetics of chlorine dioxide or chlorite were examined in humans. Chlorine dioxide is used as a drinking water disinfectant and readily forms chlorite (CIO2 ) in aqueous environments. Therefore, humans would be most likely to encounter chlorine dioxide or chlorite via the oral exposure route. Currently, available toxicokinetic information is restricted to animal studies. Additional studies could be designed to examine toxicokinetics in humans orally exposed to chlorine dioxide or chlorite. Results of human and animal studies could then provide a basis for development of PBPK models for species extrapolation. 

Toluene is mainly converted to benzyl alcohol and excreted as hippurate. Its toxicokinetics in humans have been extensively studied. 

No toxicokinetic studies have been performed on humans. Thus, the appropriateness of animals as models of white phosphorus toxicokinetics in humans is unknown. A similar tissue distribution of orally administered radiolabeled white phosphorus was observed in rats, rabbits, and mice. It seems reasonable to expect that tissue distribution in humans would be similar. No other multiple species studies were located. 

Watanabe KH, Bois FY, Daisey JM, et al. 1994. Benzene toxicokinetics in humans exposure of bone marrow to metabolites. Occup Environ Med 51 (6) 414-420. 

Toxicokinetics in humans are poorly documented but the volume of distribution is probably between 0.4-0.5 1 kg-1 the half-life (q/2) is 30-60 min. 

A mathematical model of long-term toxicokinetics in humans has been developed [14,15]. Subsequently, a more detailed description of Cd toxicokinetics was formulated considering additional events that modify the behavior of Cd in humans [16,17]. The kidney and particularly the cortex, is considered the critical target tissue for Cd and its accumulation is of decisive importance for risk assessment. In long-term exposures (life-long) either a simple one-compartment model or a more multi-compartment model predicts that 1/3 to 1/2 of the total body burden accumulates in the kidney and that the concentration of Cd in the kidney cortex is 1.25 times higher than the average concentration in the whole kidney [8]. 

Nihl n A, LofA, Johanson G (1998a) Experimental exposure to methyl tert-butyl ether Toxicokinetics in humans. Toxicol Appl Pharmacol 148 274-280 Lee C-W, Mohr SN, Weisel CP (2001) Toxicokinetics of human exposure to methyl tertiary-butyl ether (MTBE) following short-term controlled exposures. J Exp Anal Environ Epidemiol 11 67-78... 

No on-going studies were located regarding health effects or toxicokinetics in humans or animals following exposure to 1,1,2-trichloroethane. 

TABLE 8.12 Illustrative Studies of Chelatable Lead Toxicokinetics in Human Populations ... 

PbP is a relatively rapid reflection of Pb uptake and distribution toxicokinetics in human populations (NAS/NRC, 1993 U.S. EPA, 2006) and is the in vivo medium by which Pb is excreted to urine through glomerular filtration in humans. This behavior in terms of rapid exchange of Pb with target tissues and PbP makes the latter a more temporally sensitive biomarker for toxicokinetics and toxicodynamics. Little has evolved in the more current toxicological literature on Pb to quantify dose—response relationships using PbP as the dose metric beyond attempts at elucidating the exposure marker trio of PbB, PbP, and Pb in bone. 

The GDWQ for lead was first derived in 1984 as a value of 50 p.g/1, recommended for measurement at the consumer s tap. The guideline was based on some mdimentary lead toxicokinetics in human populations and the PTWI recommendation of 3 mg Pb from the 1972 Joint FAO/WHO Expert Committee on Food Additives (JECFA-FAOAVHO, 1972) for adults, adjusted somewhat for child intakes. 

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. 

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. 

Comparative Toxicokinetics. There are no data on the kinetics of diisopropyl methylphosphonate in humans. Studies in animals suggest that metabolism and urinary metabolite profiles are qualitatively similar among species. Additional studies would be useful in understanding the differences in metabolic rates in species and in determining which animal species is the most appropriate model for human exposure. 

No studies were located that examined the toxicokinetics of mineral oil, organophosphate ester, or polyalphaolefin hydraulic fluids in humans or animals, with the exception of a study examining absorption in rats after exposure to a hydraulic fluid containing 99.9% cyclotriphosphazene (Kinkead and Bashe 1987) and the absorption and metabolism of Reolube HYD46, another organophosphate hydraulic fluid (Ciba-Geigy 1985). This section, therefore, discusses available information on the toxicokinetics of major components of these classes of hydraulic fluids or of materials that maybe expected to display similar toxicokinetic properties based on similar physical and chemical characteristics. It should be emphasized that many hydraulic fluids are complex mixtures of chemicals that may include some chemicals which may not share toxicokinetic properties with the major components. 

No studies were located that examined the toxicokinetics of polyalphaolefins in humans or animals, but the similarities in physical and chemical properties between polyalphaolefins and hydrocarbons in mineral oil indicate that the toxicokinetics of polyalphaolefins may be similar to those of hydrocarbons in mineral oil hydraulic fluids. 

Comparative Toxicokinetics. The toxicokinetics database is wholly inadequate with respect to comparing toxicokinetics across species, largely because of the dearth of baseline data regarding absorption, distribution, metabolism, and excretion in any species after exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or polyalphaolefin hydraulic fluids. Also, no studies were located on the toxicokinetic properties of hydraulic fluids in humans. 

Comparative Toxicokinetics. PBPK models have not been developed to compare the toxicokinetics of hydrogen sulfide in humans and animals. Studies providing quantitative data necessary to develop PBPK models would be useful. 

The toxicokinetic and toxicological behavior of lead can be affected by interactions with essential elements and nutrients (for a review see Mushak and Crocetti 1996). In humans, the interactive behavior of lead and various nutritional factors is particularly significant for children, since this age group is not only sensitive to the effects of lead, but also experiences the greatest changes in relative nutrient status. Nutritional deficiencies are especially pronounced in children of lower socioeconomic status however, children of all socioeconomic strata can be affected. 

Mushak P. 1993. New directions in the toxicokinetics of human lead exposure. Neurotoxicology 14 29-42. 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of acrylonitrile in rats has been studied. Limited work in other species suggests that important species differences do exist. Further evaluation of these differences, and comparison of metabolic patterns in humans with those of animals would assist in determining the most appropriate animal species for evaluating the hazard and risk of human exposure to acrylonitrile. 

The database for oral exposure was insufficient to derive MRLs. Only 3 studies were located regarding neurological effects after oral exposure to /7-hexane, 2 in rats and 1 in chickens (Abou-Donia et al. 1982 Krasavage et al. 1980 Ono et al. 1981). The Krasavage study (1980) in rats resulted in aNOAEL for neurological effects of 1,140 mg/kg/day, and serious effects were seen at 4,000 mg/kg/day (hindlimb paralysis). However, since little is known about the toxicokinetics of /7-hexane after oral exposure in either humans or test animals, extrapolation of an animal study to predict health effects in humans was not attempted. 

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. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

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-... 

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