Human and Animal Data

The primary endpoint of the toxicokinetic studies is the concentration-time prohle of the substance in plasma/blood and other biological fluids as well as in tissues. The excretion rate over time and the amount of metabolites in urine and bile are further possible primary endpoints of kinetic studies, sometimes providing information on the mass balance of the compound. From the primary data, clearance and half-life can be derived by several methods. From the excretion rate over time and from cumulative urinary excretion data and plasma/blood concentration measured during the sampling period, renal clearance can be calculated. The same is the case for the bUiary excretion. 

If after single dose administration, the blood samples are not collected at time intervals, which allow for a description of the whole plasma concentration time course, including the absorption, distribution, and elimination phase, the information obtained is limited. In particular, data should be available in the hrst hours after administration to cover the absorption phase. If measurements of the parent compound and its metabolite(s) are made in this period, this will allow assessment of an extensive first pass effect, i.e., when a substance after oral administration is transported via the portal vein to the liver where metabolism takes place before the substance enters the systemic circulation. 

When data are available to enable comparison of the plasma concentration time profile after single administration with that after repeated administration, this would enable determination of whether the substance has time dependent kinetics (due to induction of metabolism, inhibition of metabolism, and/or accumulation and saturation of processes involved in distribution, metabohsm, and excretion). 

Absolute systemic bioavailabUity (absorbed fraction of the dose or concentration administered) can only be calculated by comparing the so-called Area Under the Plasma Curve (AUC, the area under the curve in a plot of the concentration of a substance in the plasma against time) after oral, inhalation, or dermal administration with the AUC after direct administration into the systemic circulation, e.g., after intravenous administration. In order to obtain a rehable estimate for AUC after single administration, it is necessary to have blood samples for 3-5 half-hves. In case data are not available for a calculation of the AUC, the absorbed fraction can be indicated from data on the amount of the parent compound and its metabohte(s) excreted in the urine, feces, and exhaled air. It should be noted that the amount excreted in the feces stems from both the unabsorbed fraction as well as from the fraction of the substance following bUiary excretion. 

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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Based on the limited human and animal data, it is not possible to predict whether or not triehloroethylene exposure at levels found in the environment and at hazardous waste sites can result in gastrointestinal effects. 

The model is based on both human and animal data. However, it is intended for applications to human dosimetry. Applications to other species would require consideration of species-specific adjustments in modal parameters. 

Nehlig A. (1999). Are we dependent upon coffee and caffeine A review on human and animal data. Neurosci Biobehav. 23, 563-676. 

Based upon the available data, derivation of AEGL-1 values was considered inappropriate. The continuum of arsine-induced toxicity does not appear to include effects consistent with the AEGL-1 definition. The available human and animal data affirm that there is a very narrow margin between exposures that result in little or no signs or symptoms of toxicity and those that result in lethality. The mechanism of arsine toxicity (hemolysis that results in renal failure and death), and the fact that toxicity in humans and animals has been reported at concentrations at or below odor detection levels (-0.5 parts per million (ppm)) also support such a conclusion. The use of analytical detection limits (0.01 to 0.05 ppm) was considered as a basis for AEGL-1 values but was considered to be inconsistent with the AEGL-1 definition. 

Reference The available human and animal data indicate that there is very little margin between seemingly inconsequential exposures and lethal exposures. The mechanism of arsine toxicity (hemolysis and subsequent renal failure) and the fact that toxicity has been demonstrated at or below the odor threshold justify the inappropriateness of AEGL-1 values for any exposure period. 

Because DMPK properties vary among different species, in vitro human and animal data and in vivo animal data cannot always be extrapolated to human in vivo responses. The three main reasons that drugs fail during clinical trials are (1) lack of efficacy, (2) unacceptable adverse effects, and (3) unfavorable ADME properties. Hence, clinical development is necessary to establish solid experiment-based human exposure and safety data through both short- and long-term monitoring. 

The excretion of chloroform and its metabolites is understood, based on human and animal data derived from oral and inhalation studies (Brown et al. 1974a Corley et al. 1990 Fry et al. 1972 Taylor et al. 1974). The major route of chloroform elimination is pulmonary, but minor pathways are through enterohepatic circulation, urine, and feces as parent compound or metabolites. There are no human or animal data regarding excretion of dermally applied chloroform. 

During the last 10 years it has been attempted to develop in vitro methods as alternative methods in the study of effects where animal models have previously been necessary. Such effects include skin and eye irritation and specific organ damage. Validation programs have been launched, and some of the above-mentioned methods have been sufficiently validated for use in regulatory risk assessment of chemical substances and may now for certain purposes be used as stand-alone evidence. Results from nonvahdated methods can in some cases be used as supportive evidence to human and animal data. 

Are both human and animal data available, and are the results consistent ... 

No inhalation MRLs were derived for 1,3-DNB or 1,3,5-TNB due to lack of human and animal data. Oral MRLs. 

TNB in humans and animals. Data on distribution via the dermal and oral routes for humans were not located. There is limited information describing distribution following acute oral exposure to... 

Both human and animal data suggest that mixed xylene, wz-xylene, o-xylene, and p-xylene all produce similar effects, although the potency with regard to a given effect may vary with individual isomers. In mice the 6-hour LC50 values for m-, 0-, andp-xylene were determined to be 5267,4595, and 3907ppm, respectively. The 4-hour LCso value for mixed xylene in rats ranged from 63 50-6700 pm. 

Available human and animal data indicate that airborne chlorine dioxide (CIO2) primarily acts as a respiratory tract and ocular irritant. Chlorite (CIO2 ) does not persist in the atmosphere either in ionic form or as chlorite salt, and is not likely to be inhaled. Potential for human exposure to chlorine dioxide or chlorite may be greatest via the oral exposure route because chlorine dioxide is sometimes used as a... 

Both the human and animal data indicate that it is unlikely that exposure to nickel in the environment or at hazardous waste sites will result in human deaths. Accidental exposure to high levels of nickel, however, may cause death. 

Althouse., R., Huff, J., Tomatis. L. and Wilbourn. J. (1980). An evaluation of chemicals and industrial process associated with cancer in humans based on human and animal data, lARC Monographs Volumes 1 to 20, Report of an lARC Working Group, Cancer Res. 40,1. 

The purpose of hazard identification is to evaluate the weight of evidence for adverse effects in humans based on assessment of all available data, ranging from observations in humans and animal data to an analysis of mechanisms of action and structure-activity relationships. Each source of information has its advantages and limitations, which determine the weight of that evidence collectively, the evidence permits a scientific judgement as to whether the chemical can cause adverse effects. 

No MRLs have been derived for inhalation exposure to PBBs because human and animal data for all durations are either insufficient or lacking. Insufficiencies in the human inhalation data include mixed-chemical and unquantified exposures. The animal inhalation database is limited by inadequately reported studies and lack of any infonnation on the mixtures likely to be most toxic (i.e., FireMaster PBBs). 

No MREs have been derived for inhalation exposure to PBDEs because available human and animal data for all durations are either insufficient or lacking. 

In attempting to correlate the human and animal data, Nolan et al. (1984) validated a physiologically based pharmacokinetic model for 1,1,1-trichloroethane. The model predicted greater absorption, blood levels and metabolism of 1,1,1-trichloroethane in rodents than in humans. On the basis of toxicokinetic data, rats were suggested to be a better model than mice to evaluate potential health effects in humans. 

The definitions of the key terms—sufficient, limited, and inadequate—are provided for both human and animal data. 

Children s Susceptibility. A limited number of human studies have examined health effects of CDDs in children. Data from the Seveso accident suggest that children may be more susceptible to the dermal toxicity of 2,3,7,8-TCDD (chloracne), but it is not known if this would be the case for other effects. Follow-up medical surveillance of the Seveso children (including measurement of serum 2,3,7,8-TCDD levels) would provide information on whether childhood exposure would pose a risk when the individual matures and ages. The available human and animal data provide evidence that 2,3,7,8-TCDD can cross the placenta and be transferred to an infant via breast milk. Although information on the developmental toxicity of CDDs in humans is limited, there are extensive animal data that the developing... 

Changes in leukocyte count and differential leukocyte count (Den Tonkelaar et al. 1983) may suggest pathological changes in lymphatic tissue, spleen, and thymus. Based on the limited human and animal data, the potential for DNOC to cause immunological effects in humans cannot be ruled out. 

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