Nature and severity of effects

The nature of an effect includes the adversity of the toxicity expressed as the level of and the basis for NOAEL and LOAEL values (Section 4.2.2), and the severity of the specific endpoint or key event (Section 4.2.3), for example judging skin irritation less severe than teratogenicity. An additional assessment factor for severe and/or irreversible effects has been proposed by various groups. This section gives an overview of such proposals and evaluations. Then, the key issues are summarized and our recommendations are presented. 

Renwick (1995) discussed the possible rationale for the use of an additional safety factor for nature of toxicity in the estimation of Acceptable/Tolerable Daily Intake (ADI/TDI) values, including a survey of the historical use of such a factor. He concluded that the principal rationale for an additional factor for nature of toxicity is to provide a greater degree of separation of the ADI/TDI from the NOAEL observed in animal studies. In scientific terms, it was recognized that there are a number of uncertainties in extrapolating from high-dose animal studies to sensitive 

Toxicological Risk Assessments of Chemicals A Practical Guide 

According to Renwick, the nature of toxicity factor was not always applied to the NOAEL for the toxicity of concern, for example  

Renwick considered that in relation to carcinogenicity for non-genotoxic chemicals and teratogenicity, the application of an extra factor for nature of toxicity is difficult to justify scientifically. He concluded that if a safety factor for nature of toxicity is to be used then logically it should be apphed to the NOAEL for the toxicity, which resulted in its use. For example, in relation to teratogenicity, a factor for nature of toxicity should be applied to the NOAEL for teratogenicity and not for maternal toxicity or some other endpoint. For carcinogenicity, the extra factor should be applied only to the NOAEL for the detection of tumors in those studies where this effect was the rationale for the use of an extra factor. In relation to a steep dose-response, it was concluded that this, in reality, concerns the precision of the NOAEL and therefore relates to the adequacy of the database rather than nature of toxicity. 

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The distinction between non-adverse effects and adverse effects can seem academic, but is essential in the hazard assessment in relation to, e.g., evaluation of no-effect levels and lowest-effect levels (Section 4.2.4), identification of the critical effect(s) (Section 4.2.7), and to the magnitude of the assessment factor to be used for taking into account the uncertainty due to the nature and severity of effects (Section 5.8). 

In conclusion, consideration should be given to the nature and severity of effects in the selection of assessment factor. However, in reahty, this should be considered in the determination of the NOAEL and LOAEL and therefore relates to the dose-response curve, see Section 5.7, rather than to the nature and severity of effects. The recommended default factor for nature and severity of effects is therefore 1. 

The easiest means for assessing occupational exposure hazards associated with materials used in a process is through the use of Permissible or Occupational Exposure Limits (OEL or PEL) which go by a variety of names for example, TLV (U.S. - American Conference of Government Industrial Hygienists), MAK (Germany), or individual company established values. Occupational exposure limits are usually set based on a combination of the inherent toxicological hazard of a chemical and a series of safety factors such as intraspecies variability in test results, nature and severity of the effect, adequacy and quality of... 

UFm accounts for the quality and relevance of the database, i.e., accounts for the uncertainties in the establishment of a NOAEL for the critical effect. The UFm includes elements such as (1) the quality of the database, e.g., data on specific toxic endpoints are lacking or inadequate, default value of 1-10 (2) route-to-route extrapolation, e.g., no studies using the appropriate exposure route are available, no default value (3) LOAEL-to-NOAEL extrapolation, e.g., a NOAEL cannot be established for the critical effect, default value of 10 (4) subchronic-to-chronic extrapolation, e.g., no chronic studies on which to establish the NOAEL are available, default value of 10 and (5) nature and severity of toxicity, e.g., the critical effect is toxicity to reproduction, carcinogenicity or sensitization, default value of up to 10. A default value for UFm has not been recommended however, a value from 1 to 100 is generally used. The value is evaluated case-by-case based on expert judgment. 

The EU TGD (EC 2003) pointed out that the nature and severity of the effect needs to be considered in the evaluation of the MOS (can be interpreted as an overall assessment factor). 

The apphcation of an extra factor for nature of toxicity is difficult to justify scientifically. Renwick (1995) concluded that if a factor for nature of toxicity is to be used then it should be apphed to the NOAEL for the toxicity which resulted in its use. Vermeire et al. (1999) considered that the type of critical effect should be taken into account but, by default, no extra correction is necessary. WHO/IPCS (1994, 1996, 1999) stated that the nature of toxicity, i.e., whether the effect is adverse or not, is considered in the determination of the NOAEL and LOAEL however, an additional factor of up to 10 could be incorporated in cases where the NOAEL is derived for a critical effect which is severe and irreversible. The EU TGD (EC 2003) pointed out that the nature and severity of the effect need to be considered in the evaluation of the MOS. TNO (Hakkert et al. 1996) considered that the biological significance of the critical adverse effect in terms of its presumable health consequence should be considered in the selection of assessment factor the default value is 1. KEMI (2003) recommended that the nature of effect should be taken into account case-by-case on expert judgment and, in comparison with other organizations, a factor of I to 10 was suggested. 

The side effects of corticosteroids range from minor to severe and life threatening. The nature and severity of... 

In the effects assessment step the relationship between the level of exposure and the incidence, nature, and severity of an (adverse) effect following the exposure is determined. For most types of effects, it is assumed that there is a minimum dose or concentration below which adverse effects will not occur the no effect level or threshold. To determine the threshold, different doses are tested, for most chemical hazards usually in laboratory animals. In toxicology, the highest tested dose without adverse effects is called the no observed adverse effect level (NOAEL). Based on the NOAEL established in an experimental study, a human limit value can be calculated, taking into account uncertainties and differences in experimental design and circumstances. Uncertainties and differences are accounted for by uncertainty factors (e.g., for interspecies differences, intraspecies variability, and exposure duration). For some types of substances, it is assumed that every level of exposure can result in adverse effects, in which case no threshold would exist. This, for instance, is assumed to apply for genotoxic carcinogens. 

The nature and severity of the toxicity that may result from mercury exposure are functions of the magnitude and duration of exposure, the route of exposure, and the form of the mercury or mercury compound to which exposure occurs. Since the ultimate toxic species for all mercury compounds is thought to be the mercuric ion, the kinetics of the parent compound are the primary determinant of the severity of parent compound toxicity. It is differences in the delivery to target sites that result in the spectrum of effects. Thus, mercury, in both inorganic and organic forms, can be toxic to humans and other animals. 

Chemicals do, however, differ greatly in their capacity to produce toxicity. The conditions of exposure under which toxic effects are produced - the size of the dose and the duration of dosing needed -vary greatly among chemicals. Moreover, the nature and severity of the toxic effects produced are also highly varied, and are different not only for different chemicals, but also for a single chemical as the conditions of exposure to it change. 

The likelihood for the development of symptoms following inhalation exposure and the nature and severity of respiratoiy tiact injuiy depends on a number of factors, which include the chemical namre of the smoke, concentration and toxic potency of inhaled materials, particle size and vapor proportion, duration of exposure, water solubility, respiratory minute volume, and personal characteristics (e.g., differential susceptibility, exertion). During training and operational use, exercise will result in an increased respiratory minute volume (effect of tachypnea and increased tidal volume) and thus a greater inhalation exposure dose. Most of the more soluble inhaled material will tend to predominantly affect the upper airways, and the less soluble materials affect mainly the peripheral airways and alveoli. 

The types, site, incidence, and severity of effects and the nature of the exposure- or dose-response relationship are also taken into account. In assessing potential to induce tumors in humans, aspects that add to the weight of evidence include (a) observation of uncommon tumor types, (b) occurrence of tumors at multiple sites by more than one route of administration in multiple strains, sexes, and species, and (c) progression of lesions from preneoplastic to benign to malignant, including metastases and comparatively short latency periods. 

In evaluating the reasonable necessity for a standard, the Commission has a duty to take a hard look, not only at the nature and severity of the risk, but also at the potential the standard has for reducing the severity or frequency of the injury, and the effect the standard would have on the utility, cost or availability of the product. In this case, the Commission neglected that duty. [569 F.2d at 844.]... 

Corroborative information is not reportable, but to be corroborative the information must substantially duplicate or confirm a prior result. The route of exposure, dose, species, strain, and sex of the test animal, time to onset of effect, nature, and severity of the effect must be the same. Similarly, a well-recognized and well-established serious adverse effect need not be reported. However, observations of known effects during an emergency incident of environmental contamination may be reportable. 

Undesirabie effects Addition of newly-recognised ADRs improving information about the nature, frequency and severity of effects already listed... 

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