Toxicity toxicokinetics

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

There is limited information about the toxicity, toxicokinetics, and toxicological properties of onchidal and additional data are needed to make a health effects-based risk assessment of the natural compound. Although fasciculins are much better known, data on toxicological properties and toxicokinetics will be of interest and usefiil for risk assessments despite it being generally accepted that the toxicity of this proteinic toxin occurs at very low doses. 

Haber, Lynne has more than 12 years of experience in applying risk assessment methods in evaluating the toxicity, toxicokinetics, and mode of action of chemicals. Her current interests are in the application of mechanistic information in risk assessment and in methods for extending the dose-response curve to low doses. Other current work includes research on children s risk issues, consideration of mode of action in cancer risk assessment, incorporating data on polymorphisms into risk assessment, and development of scientifically based occupational exposure limits. 

There is limited information about the toxicity, toxicokinetics, and toxicological properties of onchidal, and additional data are needed to make a health-effect-based... 

The kinetic properties of chemical compounds include their absorption and distribution in the body, theit biotransformation to more soluble forms through metabolic processes in the liver and other metabolic organs, and the excretion of the metabolites in the urine, the bile, the exhaled air, and in the saliva. An important issue in toxicokinetics deals with the formation of reactive toxic intermediates during phase I metabolic reactions (see. Section 5.3.3). 

S3A Note for Guidance on Toxicokinetics The Assessment of Systemic Exposure in Toxicity Studies... 

Pharmacokinetics concerns the fate of a dmg in the body at the approximate therapeutic dose range, while toxicokinetics assesses behaviour at the higher dose levels associated with toxic effects. The fate of a dmg is dictated by the rates of ... 

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. 

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. 

Practically all toxicokinetic properties reported are based on the results from acute exposure studies. Generally, no information was available regarding intermediate or chronic exposure to methyl parathion. Because methyl parathion is an enzyme inhibitor, the kinetics of metabolism during chronic exposure could differ from those seen during acute exposure. Similarly, excretion kinetics may differ with time. Thus, additional studies on the distribution, metabolism, and excretion of methyl parathion and its toxic metabolite, methyl paraoxon, during intermediate and chronic exposure are needed to assess the potential for toxicity following longer-duration exposures. 

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the living organism. 

Species The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. 

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. 

The toxicity of chemicals to living organisms is determined by the operation of both toxicokinetic and toxicodynamic processes (Chapter 2). The evolution of defense mechanisms depends upon changes in toxicokinetics or toxicodynamics or both, which will reduce toxicity. Thus, at the toxicokinetic level, increased storage or metabolic detoxication will lead to reduced toxicity at the toxicodynamic level, changes in the site of action that reduce affinity with a toxin will lead to reduced toxicity. 

For convenience, the processes identified in Figure 2.1 can be separated into two distinct categories toxicokinetics and toxicodynamics. Toxicokinetics covers uptake, distribution, metabolism, and excretion processes that determine how much of the toxic form of the chemical (parent compound or active metabolite) will reach the site of action. Toxicodynamics is concerned with the interaction with the sites of action, leading to the expression of toxic effects. The interplay of the processes of toxicokinetics and toxicodynamics determines toxicity. The more the toxic form of the chemical that reaches the site of action, and the greater the sensitivity of the site of action to the chemical, the more toxic it will be. In the following text, toxicokinetics and toxicodynamics will be dealt with separately. 

As discussed earlier, selectivity is the consequence of the interplay between toxicokinetic and toxicodynamic factors. Some examples are given in Table 2.8, which will now be briefly discussed (data from Walker and Oesch 1983, and Walker 1994a,b). These and other examples will be described in more detail under specific pollutants later in the text. In the table, comparisons are made between the median lethal doses or concentrations for different species or strains. Comparisons are made of data obtained in lethal toxicity tests where the same route of administration was used for species or strains that are compared. The degree of selectivity is expressed... 

The problem of potentiation was discussed earlier (Chapter 2, Section 2.5). Potentiation is often the consequence of interactions at the toxicokinetic level, especially inhibition of detoxication or increased activation. The consequences of such potentiation may be evident not only at the whole animal level but also in enhanced responses of biomarker assays that measure toxicity (Figure 13.3). By contrast, biomarkers of exposure alone are unlikely to give any indication of potentiation at the toxicokinetic level. 

Toxicokinetics Relating to the fate of toxic chemicals within living organisms— that is, questions of uptake, distribution, metabolism, storage, and excretion factors that determine how much of a toxic form reaches the site of action. 

Toxicological Chronic toxicity Carcinogenicity Fertility study (multi-generation) Embryotoxicity (non-rodent) Acute/subacute toxicity in 2nd species Toxicokinetics... 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

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. 

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