INDEX carcinogenic effects

To assess die overall potential for non carcinogenic effects posed by several exposure pathways, the total haziird index for each exposure duration (i.e., chronic, subchronic, and shorter-term) should be calculated separately. This equation is described below ... 

Chronic daily intake (CDI), Hazard Index (HI), and Cancer Risk (CR) for carcinogenic effects were calculated and exposures associated with HI<1 and CRdE-6 were considered negligible. 

Carcinogenicity has been used by the World Health Organization as an index for classifying mycotoxins [32]. However, the carcinogenic effects of very few mycotoxins have been established or even directly correlated. Therefore, this method of classifying mycotoxins may not be applicable at the present time. But as the carcinogenic risk of more mycotoxins is established based on ongoing research to identify the associations between human or animal consumption of contaminated food and the incidence of associated mycotoxicosis, this classification system may become very relevant. 

Risk Characterization. Once a quantitative exposure assessment has been made, Risk Assistant allows the user to automatically calculate lifetime excess cancer risk and/or a hazard index for toxic non-carcinogenic effects of chronic exposure for any agent included in the toxicity databases which currently include about 300 compounds. The appropriate hazard values (slope-potency factors and reference doses) for the relevant routes of exposure are automatically retrieved from the databases. The uncertainty calculations in the exposure assessment can also be retrieved to assess the range of risks associated with a given exposure situation. 

It is important to calculate die hazard index separately for clironic, subclironic, and short-temi exposure periods as described below. It is also important to remember to include RfDs for die noncancer effects of carcinogenic substances. 

Aristolochic acid was tested for therapy of tuberculosis, chronic bronchitis, bronchial asthma, pneumocardial diseases, etc. Clinical results showed curative effects, and the index of immune function of cases increased significantly compared to the control group (111). In Germany, an aristolochic acid preparation called Tardolyt that had been used as an antiinflammatory was canceled due to its potential carcinogenicity (72). 

The risk index for any hazardous substance in Equation 1.1 or 1.2 (see Section 1.5.1) is calculated based on assumed exposure scenarios for hypothetical inadvertent intruders at near-surface waste disposal sites and a specified negligible risk or dose in the case of exempt waste or acceptable (barely tolerable) risk or dose in the case of low-hazard waste. Calculation of the risk index also requires consideration of the appropriate measure of risk (health-effect endpoint), especially for carcinogens, and the appropriate approaches to estimating the probability of a stochastic response per unit dose for carcinogens and the thresholds for deterministic responses for noncarcinogens. Given a calculated risk index for each hazardous substance in a particular waste, the waste then would be classified using Equation 1.3. 

Risk Index for Mixtures of Hazardous Substances. For the purpose of developing a comprehensive and risk-based hazardous waste classification system, a simple method of calculating the risk posed by mixtures of radionuclides and hazardous chemicals is needed. The method should account for the linear, nonthreshold dose-response relationships for radionuclides and chemical carcinogens (stochastic effects) and the threshold dose-response relationships for noncarcinogenic hazardous chemicals (deterministic effects). 

Risk index for mixtures of substances that cause stochastic effects (carcinogens). The risk index for mixtures of substances that cause stochastic effects (radionuclides and chemical carcinogens) takes into account the risk in all organs or tissues, and it assumes that the risk in any organ is independent of the risk in all other organs. The risk index for mixtures of substances causing stochastic effects can be represented as ... 

The risk index in Equation 6.2 is expressed in terms of risk (i.e., the probability that an adverse response will occur during an individual s lifetime). This definition is consistent with the fundamental objective of developing a risk-based hazardous waste classification system. However, the use of health risk per se in calculating the risk index presents some difficulties because risk is not proportional to dose for substances that cause deterministic effects. For this type of substance, the risk is presumed to be zero at any dose below a nominal threshold. Since the allowable dose should always be less than the threshold in order to prevent the occurrence of adverse responses, expressing the risk index in terms of risk would result in an indeterminate value and, more importantly, a lack of distinction between doses near the nominal thresholds and lower doses of much less concern. For any hazardous substance, including carcinogens for which risk is assumed to be proportional to dose without threshold, it is generally useful to express the risk index as the ratio of a calculated dose [e.g., sieverts, mg (kg d)-1] to an allowable dose that corresponds to an allowable risk ... 

Sundaram, S. Dayan, A.D. Effects of a cholecystokinin receptor antagonist on rat exocrine pancreatic response to raw soya flour. Human Exp. Toxicol. 1991,10, 179-182. Expert Working Group (Safety) of ICH. FDA Guidance for Industry ich-slc dose selection for carcinogenicity studies of pharmaceuticals. Drug Information Branch, HFD-210, CDER, 5600 Fishers Lane, Rockville, MD 20857 accessed Sept. 22, 1998, http //www.fda.gov/CDER/ guidance/index, htm. 

Noncarcinogenic Effects. These effects are assessed only if the carcinogenic indicator compounds are not detected or are below regulatory criteria. The following petroleum hydrocarbon fractions, minus the carcinogenic indicator compounds, were selected as representing compounds with similar transport properties. Toxicity values for constituents of the fraction or for a similar mixture were selected to represent the toxicity of the fraction. Aromatic and aliphatic hydrocarbons are considered separately and further subdivided on the basis of equivalent carbon number index (EC). This index is equivalent to the retention time of the compounds on a boiling point GC column (non-polar capillary column), normalized to the //-alkanes. Physical and chemical properties of hydrocarbons that are... 

C = carbon number EC = Equivalent Carbon Number Index MRL = minimal risk level NA = not applicable NV = not verifiable the health effects data for this compound were reviewed by the EPA RfD/RfC Work Group and determined to be inadequate for the derivation of an RfC (EPA 1998b) WOE = weight-of-evidence classification for carcinogenicity... 

The mixture total is less than 1, therefore it has not exceeded liver endpoint for toxicity. Note that using the hazard index does not take into account synergistic or antagonist effect of multiple chemicals. A hazard index is not used for carcinogenic risk for chemical mixtures. If the chemicals are carcinogenic, their cancer slopes can be added together when calculating risk. 

---