Duration of Exposure Extrapolation

The most relevant study to base a hazard assessment and derivation of a tolerable intake upon is a study that reflects the human exposure situation as well as possible. In many cases a lifelong exposure is the most relevant exposure scenario for humans and a hfetime animal study (in practice a chronic study) is the most relevant study on which to base the assessment. In other situations where the expected human exposure is of limited duration, for example in seasonal work with plant protection products lasting 2 or 3 months per year, or occasionally, for example use of certain consumer products, the assessment should preferably be based on studies of shorter duration. 

For numerous chemicals, a lifetime or chronic study may not be available for the assessment. In such cases it may be necessary to base the assessment on data from a shorter duration study, e.g., a 90-day study and then the lack of data from a long-term study needs to be accounted for in the assessment. Assessment factors of 1 to 10 have been suggested or apphed by various national and 

Toxicological Risk Assessments of Chemicals A Practical Guide 

Dourson and Stara (1983) evaluated ratios of subchronic to chronic exposure for either NOAELs (30 ratios), LOAELs (22 ratios), or their combination (52 ratios) derived from the toxicity studies compiled by Weil and McCoUister (1963), see above. For more than half of the observed chemicals, ratios were 2 or less, and approximately 96% of the ratios were below a value of 10. According to the authors, this supports a 10-fold UF to account for estimating an ADI from a subchronic effect level for a chemical if a chronic level is unavailable. 

Woutersen et al. (1985, as cited in Kalberlah and Schneider 1998 ECETOC 1995, 2003) evaluated toxicity data relating to 82 substances including stabilizers, plasticizers, antioxidants, disinfectants, food additives, pesticides, other agrochemicals, and industrial chemicals. The substances were each tested (oral administration to rats) for a subacute (2-4 weeks) and a subchronic (13-18 weeks) duration of exposure. Both the NOAEL and the LOAEL were included in the comparison. For 56% of the substances (46), the ratio NOAELsubacute/ NOAELsubchronic was about 1. For 44% of the substances (36), the subchronic NOAEL was lower than the subacute NOAEL (i.e., the ratio was above 1), and for 3/82 substances, the ratio was above 100. The 95th percentile was about 10. A factor of 4 covered 70%-80% of the substances. 

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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. 

In some cases, the duration of exposure that is or might be experienced by the population of interest might not match that involved in the study. So, for example, dose-response information from relatively short-term exposures might in some cases be the only available information when the concern is long-term, or even lifetime exposure in the population that is the subject of the risk assessment. If the risk assessment is to be completed before new, long-term data can be developed, some justification will have to be found for extrapolation of the short-term data to estimate the consequences of long-term exposure. 

In a report on a research project quantification of extrapolation factors (Kalberlah and Schneider 1998), it is noted that extrapolation factors are intended to replace lack of knowledge by a plausible assumption, and that instimtions with responsibihty for establishing the mles must decide which level of statistical certainty, e.g., applicable for 50% or for 90% of a representative selection of substances, is desired for the selection of a standard value. It is furthermore noted that extrapolation factors are required for (1) time extrapolation, e.g., from a subchronic to a chronic duration of exposure (2) extrapolation from the LOAEL to the NAEL (3) interspecies extrapolation, i.e., from experimental animals to humans and (4) intraspecies extrapolation, i.e., from groups of persons with average sensitivity to groups of persons characterized by special sensitivity. In addition to these extrapolations, route-to-route extrapolation, e.g., oral-to-inhalation or dermal-to-oral must also be discussed. 

On average, a factor of 2-3 was considered sufficient for time extrapolation from a subchronic to a chronic duration of exposure. A higher factor is required in order to cover the 90th percentile. 

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. 

Attention is also drawn to the fact that there are some other elements not included in the traditional assessment factor of 10 including adequacy of the database, nature of the effect, duration of exposure, route-to-route extrapolation, and considerations of extra-sensitive subpopulations such as children, the elderly, and patients under medical treatment. 

Vermeire et al. (1999) reviewed several studies comparing NOAELs from chronic and subacute/subchronic studies in order to evaluate the distribution of the extrapolation factor for duration of exposure. The ratios of observed NOAELs from oral studies using historical data for various compounds were calculated. The most likely distribution of the ratios was considered to be lognormal and the parameters of the distributions of the ratios were estimated, see Table 5.8. 

The authors noted that it may be expected that the NOAELs from subacute/subchronic smdies tend to be larger than NOAELs from chronic studies and it was considered that the GM ratios for the NOAELs assessed in the studies most likely overestimated the median of the distribution of the extrapolation factor for duration of exposure. The authors also noted that it is very likely that the databases used in these studies overlap each other significantly. It was also pointed out that the distributions presented in Table 5.8 were based on rather variable exposure periods for the subchronic NOAELs, included interspecies variation (no matching for species) for... 

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). 

For those substances for which appropriate human smdies are available, the so-called average relative risk model has been used. Quantitative assessments using this model comprises four steps (1) selection of studies (2) standardized description of study results in terms of relative risk, exposure level, and duration of exposure (3) extrapolation towards zero dose and (4) application to a general (hypothetical) population. 

If proper safeguards are to be maintained economically, it is essential to define the extent of the hazard and identify the problem areas. Research is needed to determine the sites and duration of exposure and to measure the amounts of residues and their rates of dissipation. Such measurements can be made with precision. The problem is to use knowledge gained in a particular situation to provide guidelines or models which can be applied more generally to field operations. Such extrapolations are controversial and they may also be dangerous if they are in error. The symposium includes descriptions of techniques for measurement of exposure, and some contributors indicate the controversial aspects of solutions that have been proposed. 

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. 

Adequate extrapolation of results from standard laboratory toxicity tests to other time scales of exposure and response requires observations on the time course of toxic effects. These observations can then be used to construct time-to-event models, such as the DEBtox model mentioned above. These models explicitly address both intensity and duration of exposure to hazardous chemicals, and better use is made of the data gathered from toxicity experiments. Diverse endpoints in time can be addressed, and individual organism characteristics and/or environmental circumstances (e.g., temperature) can be incorporated as covariables. An overview of time-to-event models and approaches and their use in the risk assessment of chemicals is provided by Crane et al. (2002). 

Describe the route, level, stage, and duration of exposure as compared with expected human exposures, including available toxicokinetic data used to extrapolate across routes of exposure. 

The guidance values proposed refer basically to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber s rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment should be done on a case-by-case basis e.g. for a 28-day study the guidance values below would be increased by a factor of three. 

ATSDR develops MRLS for specified durations of exposure, and generally does not extrapolate among durations. Therefore, an uncertainty factor for extrapolation between subchronic and chronic exposures is not used. 

Additional studies or pertinent information which lend support to this MRL Inhaled metallic mercury is quickly absorbed through the lungs into the blood. Its biologic half-life in humans is approximately 60 days, with the half-life varying with the physiological compartment (e.g., 21 days in the head, versus 64 days in the kidneys Cherian et al. 1978). Since the duration of exposure does influence the level of mercury in the body, the exposure level reported in the Fawer et al. (1983) occupational study was extrapolated from an 8-hour/day, 40-hour/workweek exposure to a level equivalent to a continuous 24 hour/day, 7 days/week exposure as might be encountered near a hazardous waste site containing metallic mercury. 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

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