Data from Studies in Experimental Animals

DATA FROM STUDIES IN EXPERIMENTAL ANIMALS 3.3.1 Animal Toxicity Studies... 

Finally, the use of different types of information (human data, data from studies in experimental animals, in vitro test data, and other data such as, e.g., data on physico-chemical properties and (Q)SAR) in the hazard assessment for a specific endpoint is addressed in more detail. 

Data from studies in experimental animals are the typical starting points for hazard and risk assessments of chemical substances and thus differences in sensitivity between experimental animals and humans need to be addressed, with the default assumption that humans are more sensitive than experimental animals. The rationale for extrapolation of toxicity data across species is founded in the commonality of anatomic characteristics and the universality of physiological functions and biochemical reactions, despite the great diversity of sizes, shapes, and forms of mammalian species. 

Extrapolation of data from studies in experimental animals to the human situation involves two steps a first step is to adjust the dose levels applied in the experimental animal studies to human equivalent dose levels, i.e., a correction for differences in body size between laboratory animals and humans. A second step involves the application of an assessment factor to compensate for uncertainties inherent in toxicity data as well as the mterspecies variation in biological susceptibility. These two steps are addressed in the following sections. 

Previously the LMS model (Section 6.2.1.2) was the most widely adopted approach for low-dose extrapolations for data from studies in experimental animals. More recently, an MOE approach has... 

A.7.2.2.3 For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall be from well conducted epidemiological studies, if available, which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans may be sufficient for a Category 1A classification if supplemented with adequate data from studies in experimental animals, but classification in Category 1B may also be considered. 

One aspect in the extrapolation of data from smdies in experimental animals to the human simation is, as mentioned above, a correction of the dose levels in experimental animal smdies to equivalent human dose levels, e.g., a NOAEL derived from an animal study to the equivalent human NOAEL. 

Today, well over 100 biological parameters of mammals are known to be linearly related to body weight and highly predictable on an mterspecies basis (Davidson et al. 1986, Voisin et al. 1990, Calabrese et al. 1992). The allometric equation has traditionally been used for extrapolation of experimental data concerning physiological and biochemical functions from one mammalian species to another. In addition, the allometric equation has also been used extensively as the basis for extrapolation, or scaling, of e.g., a NOAEL derived for a chemical from studies in experimental animals to an equivalent human NOAEL, i.e., a correction for differences in body size between humans and experimental animals. 

The most frequently used POD for threshold effects (Section 4.2) is the NOAEL (Section 4.2.4). This NOAEL is generally obtained from studies in experimental animals. If reliable human data are available to derive the NOAEL, this value is preferable to the NOAEL from experimental animals. Where a NOAEL cannot be derived, a LOAEL, if available, can be used. An alternative POD to the NOAEL/LOAEL is the benchmark dose (BMD) (Section 4.2.5). The tolerable intake can also, in some cases, form the basis as the POD. In this chapter, the POD will be denoted as a derived no-effect level (DNEL) in order to provide a general term for the various types of PODs that can form the basis for the risk characterization. 

Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals-by any relevant route of exposure-might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially misleading if uptake through the skin is not documented. Such a study would be insufficient for risk assessment, especially if it were interpreted as a negative study (one that showed no adverse effect). In studies where developmental toxicity is detected, regardless of the route of exposure, skin absorption data can be used to establish the internal dose in the pregnant animal for risk extrapolation to human dermal exposure. For a discussion pertinent both to the development and to the application of pharmacokinetic data, risk assessors can consult the conclusions of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies (Kimmel and Francis 1990). 

The data summarized in this chapter show that A3 receptors are present in immune cells and are indeed involved in the physiopathologic regulation of inflammatory and immune processes. However results from in vitro and in vivo studies in experimental animals suggest activation of the A3 subtype can be both pro or anti-inflammatory depending on ... 

When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture can be classified by weight of evidence evaluation of this data. Care should be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive. 

Human data on the transport of Cd in the circulation from the site of absorption to the various organs are scarce. Following absorption in the lungs and/or intestine, Cd in the blood initially primarily binds to albumin and other thiol-containing high- (HMW) and low-molecular-weight (LMW) proteins in the plasma, including MT, as well as to blood cells [23]. Studies in experimental animals show that immediately after parenteral administration, most of the Cd is present in the plasma... 

The effects of endosulfan have not been studied in children, but they would likely experience the same health effects seen in adults exposed to endosulfan. Data in adults, mostly derived from cases of accidental or intentional acute exposure (ingestion) to large amounts of endosulfan, indicate that the primary target of endosulfan toxicity is the nervous system. The effects are manifested as hyperactivity and convulsions and in some cases have resulted in death (Aleksandrowicz 1979 Blanco-Coronado et al. 1992 Boereboom et al. 1998 Cable and Doherty 1999 Lo et al. 1995 Terziev et al. 1974). These effects have been reproduced in experimental animals. 

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