Exposure extrapolation duration

Stages in hazard characterization according to the European Commission s Scientific Steering Committee are (1) establishment of the dose-response relationship for each critical effect (2) identification of the most sensitive species and strain (3) characterization of the mode of action and mechanisms of critical effects (including the possible roles of active metabolites) (4) high to low dose (exposure) extrapolation and interspecies extrapolation and (5) evaluation of factors that can influence severity and duration of adverse health effects. 

The uncertainties fall into two broad categories. Firstly, there are the uncertainties related to the extrapolation of the key data from experimental animal species to the average human (animal-to-human), and then from the average human to other members of the population with different characteristics (human-to-human), i.e., those with greater sensitivity. Secondly, there are then a number of uncertainties related to the available database including those arising from route-to route extrapolation, duration of exposure, NOAEL not established or not firmly established, and gaps or other deficiencies in the database. 

The authors also pointed out the connection between the duration of exposure extrapolation factor and the interindividual variance. If, e.g., young adult animals were exposed (normal case) and observed over 90 days, this might have to be assessed differently from a smdy on neonates or older animals. Therefore, it is necessary to examine which elements have already been included in the interindividual factor. If the time factor (children, elderly people) was considered as a separate subfactor in the interindividual factor, then the specific data on the exposure period must be considered in relation to the duration of exposure extrapolation factor in order to avoid double assessment. 

Duration-of-Exposure Extrapolation, Systemic Effects, Overall Evaluation... 

For systemic effects, ECETOC (2003) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. 

WHO/IPCS (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

Although for a variety of reasons extrapolation from experimental animals to humans presents problems, including differences in metabolic pathways, dermal penetration, mode of action, and others, experimental animals present numerous advantages in testing procedures. These advantages include the possibility of clearly defined genetic constitution and their amenity to controlled exposure, controlled duration of exposure, and the possibility of detailed examination of all tissues following necropsy. 

The quantitative description of actual empirical data of the concentration-duration relationship can be expressed by any of a number of linear regression equations. In the assessment of empirical data reported by ten Berge et al. (1986), these workers quantified the exposure concentration-duration relationship by varying the concentration to the n power. Since raising c or t or both to a power can be used to define quantitatively the same relationship or slope of the curve and to be consistent with data and information presented in the peer-reviewed scientific literature, the equation C x t = k is used for extrapolation. It must be emphasized that the relationship between C and t is an empirical fit of the log transformed data to a line. No conclusions about specific biologic mechanisms of action can be drawn from this relationship. 

Use of Exposure Data Matrices to Reconstruct Exposures. Exposure data or job exposure matrices have been used since the 1940s, and continue to be a valuable method for exposure reconstruction (Coughlin and Chiazze 1990). A job exposure matrix (JEM) aims to incorporate aU somces of available data in order to link information about job categories and likely exposures (Coughlin and Chiazze 1990). The types of information used in a JEM, if available, include exposure data, current data combined wilh otho- information extrapolated to previous job tasks or working conditions, exposure time durations, job titles, work locations or... 

Verification of Uncertainty Factors. As summarized in several publications, uncertainty factors are currently recommended to estimate acceptable intakes for systemic toxicants (1,13,18). The selection of these factors in general reflects the uncertainty inherent with the use of different human or animal toxicity data (i.e., the weight of evidence plays a major role in the selection of uncertainty factors). For example, an uncertainty factor of less than 10 and perhaps even 1 may be used to estimate an ADI if sufficient data of chronic duration are available on a chemical s critical toxic effect in a known sensitive human population. That is to say that this ideal data base is sufficiently predictive of the population threshold dose therefore, uncertainty factors are not warranted. An overall uncertainty factor of 10 might be used to estimate an acceptable intake based on chronic human toxicity data and would reflect the expected intraspecies variability to the adverse effects of a chemical in the absence of chemical-specific data. An overall uncertainty factor of 100 might be used to estimate ADIs with sufficient chronic animal toxicity data this would reflect the expected intra- and interspecies variability in lieu of chemical-specific data. However, this overall factor of 100 might be used with subchronic human data in this case the 100-fold factor would reflect intraspecies variability and a subchronic exposure extrapolation. 

There are several limitations to tliis approach that must be acknowledged. As mentioned earlier, tlie level of concern does not increase linearly as the reference dose is approached or exceeded because the RfDs do not luive equal accuracy or precision and are not based on the same severity of effects. Moreover, luizm-d quotients are combined for substances with RfDs based on critical effects of vaiy ing toxicological significance. Also, it will often be the case that RfDs of varying levels of confidence Uiat include different uncertainty adjustments and modifying factors will be combined (c.g., extrapolation from animals to hmnans, from LOAELs to NOAELs, or from one exposure duration to anoUier). 

Hazard characterization is a quantitative or semi-quantitative evaluation of the nature, severity, and duration of adverse health effects associated with biological, physical, or chemical agents that may be present in food. The characterization depends on the nature of the toxic effect or hazard. Eor some hazards such as genotoxic chemicals, there may be no threshold for the effect and therefore estimates are made of the possible magnitude of the risk at human exposure level (dose-response extrapolation). 

Reliable NOAELs and LOAELs for intermediate oral exposure are restricted to a 90-day NOAEL of 50 mg/kg/day for systemic toxicity in rats (a species that is not sensitive to the neuropathic effects of organophosphate esters) exposed to Pydraul 90E for 90 days and NOAELs and LOAELs for delayed neuropathy in chickens exposed to Durad 110. In chickens exposed to Durad 110 for 28 days, a NOAEL of444 mg/kg/day and LOAEL of 1,333 mg/kg/day were identified (FMC 1986) when the duration was increased to 90 days, the NOAEL was 20 mg/kg/day and the LOAEL was 90 mg/kg/day (FMC 1986). These data are inadequate for derivation of an intermediate oral MRL for organophosphate ester hydraulic fluids. As discussed under the acute-duration oral MRL section, there is uncertainty regarding extrapolation of chicken doses to human doses. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability and extrapolation of data from laboratory animals to humans. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer end point for each exposure duration. MRLs include adjustments to reflect human variability and, where appropriate, the uncertainty of extrapolating from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et al. 1987 EPA 1989a), uncertainties are associated with the techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of these procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. 

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