Non-Cancer Effects of Chemicals

For the non-cancer effects of chemicals, a reference dose (RfD) is used. An RfD is a threshold dose below which adverse effects are not expected. The RfD is based on the assumption that adverse effects will only occur when certain physiological mechanisms are overcome, and will only occur above a certain level. Therefore, there are some doses that are indeed safe because toxic effects should not occur below these levels. In addition, we saw in chapter 7 the numerous uncertainty factors used to generate these values, which has the effect of assuming the chemicals are substantially more toxic to humans than other species. 

Unlike for SFs, the lower the RfD the more potent the chemical. One of the lowest RfDs is for tetraethyl lead, an organic form of lead that can enter the central nervous system and impact intelligence. This form of lead may have led to the mental problems of some of the early Roman emperors (see chapter 1). One of the highest RfDs is for xylenes, a common ingredient of gasoline. RfDs for these two chemicals differ by a factor of about 10, or 100,000. This means that tetraethyl lead is 100,000 

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For the non-cancer effects of chemicals, risks or probabilities of effects are not estimated. This is because, unlike the assumption of no threshold used for cancer chemicals, there are doses below which no adverse effects are expected from chemical exposure for non-cancer effects of chemicals. Instead of generating a risk, the estimated dose is divided by the reference dose, which is considered a safe level below which toxicity is not expected to occur. The result of this division is a ratio that will either be above or below one. This ratio is referred to either as a hazard quotient, if only one chemical is considered, or a hazard index, if multiple chemicals are included. If the ratio is below one, this means that the estimated dose is below the threshold dose, and no toxicity is expected. If the ratio is above one, the estimated dose is above the threshold dose, and toxicity may result. Ratios above one do not mean that toxicity will resnlt, but that there is a chance of this occurring. The higher the ratio is above one, the greater the chance that toxicity can result from exposure. 

Therefore, calculation of excess risk is only relevant for cancer effects of chemicals. For all other effects, there is either no risk (if the ratio is below one), or some degree of likelihood that adverse effects can occur (if the ratio is above one). This degree of likelihood for non-cancer effects of chemicals is typically referred to cis hazard. Regulatory agencies typically manage the non-cancer effects of chemicals so that concentrations at a site resnlt in ratios no greater than one. Therefore, non-cancer effects would not be expected from chemical exposure at properly managed sites. 

The risk characterization step involves two components risk estimation and risk description. The risk estimation component is similar to the hnman health risk characterization conducted for non-cancer effects of chemicals in that it qnantifies potential effects from chemical exposure. Depending on the methods nsed to estimate exposure and toxicity, the methods nsed in risk estimation for ecological receptors may differ from those used for humans. One method that can be used, which is similar to the method used for humans, is the toxicity quotient method. In this method, the estimated exposure is divided by a safe level of exposure developed in the characterization of effects component. The resulting value is compared to a threshold level of one. Below this level, no effects are expected (regardless of what the impact might be). Above this level, there may be effects. 

This report assesses the potential non-cancer and cancer effects of chemical agent GA (CAS No. 77-81-6). 

Toxicity values are separately developed for different exposure routes. Typically, values are developed for the oral and inhalation routes of exposure because the majority of toxicity studies are based on these exposure routes. In most cases, the oral values are used for the skin exposure route, adjusted for decreased absorption across the skin relative to the oral route. Two types of toxicity values are currently used in risk assessment those describing cancer potency and those for non-cancer effects. Some chemicals are known to have both cancer and non-cancer effects. In these situations, both cancer and non-cancer values might be developed. Therefore, each chemical might have up to four toxicity values. Toxicity values for cancer and non-cancer effects are separately discussed below. 

Non-cancer toxicity inciudes effects that injure specific or multiple organs or systems (e.g., alcohol and the liver, lead and the nervous system). The mechanisms are almost as numerous as the number of chemicals. Specific effects and examples of chemicals that cause them are discussed in chapter 4. The mciin point to mcike here is that, for non-cancer effects, a threshold level is assumed. Below this threshold level, no toxic effects are expected because there is not enough chemical present to overcome the defense mechanisms of the cell, organ, or system. Above this threshold level, toxic effects may occur because the defense mechanisms are overwhelmed. 

This chapter builds on the basic concepts presented in chapter 3 and discusses the types of cancer and non-cancer effects that can occur from chemical exposure. It provides an overview of specific effects of some well-known chemicals, and relates these effects to the mechanisms of toxic action discussed in chapter 3. Effects on humans will be discnssed first, followed by effects on other species (i.e., ecological effects). 

So far, we have only discussed dose extrapolation for non-Ccmcer chemicals. The same uncertainties discussed for dose extrapolation of non-cancer effects cu e also relevant for cancer effects. Mathematical models are typically used to extrapolate relationships from dose and cancer incidence established using high laboratory doses to those at low doses. These models can range from relatively simple linear equations (e.g., a straight line is assumed to represent the relationship) to complex mathematical solutions that involve exponential terms and knowledge of calculus. These models differ in their complexity based on the amount of information known about how a chemical causes cancer. Since the process of cancer development is complex, it is not surprising that some of the models used to describe the relationships between dose and response are also complex. 

The process of identifying chemical healtli liazards should also incorporate the near term (release into tlie environment) and long term fate of the chemical health hazard following entry into the human body. Non-carcinogcnic effects include all toxicological responses except tumors. Not all tumors are cancerous. Malignant tumors are cancerous and spread, or metastasize, to surrounding structures. 

To assess tlie overall potential for noncarcinogenic effects posed by more dian one chemical, a liazard index (HI) approach has been developed based on EPA s Guidelines for Healdi Risk Assessment of Chemical Mixtures. This approach assumes that simultaneous subtlu eshold exposures to several chemicals could result in an adverse healtli effect. It also assumes tliat tlie magnitude of the adverse effect will be proportional to tlie sum of the ratios of the subtlireshold exposures to acceptable exposures. The non cancer hazard index is equal to tlie sum of the hazard quotients, as described below, where E and tlie RfD represent the same exposure period (e.g., subclironic, clironic, or shorter-term). 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to non-threshold effects such as cancer. 

Figure 5.10 Difference in the dose-effect models for humans and species assemblages (species sensitivity distribution [SSD], right). Threshold-type curves are used for many compounds it is assumed that below a certain daily intake there will be no effects. Nonthreshold chemicals (i.e. certain types of carcinogens) lead to increased probability of cancer, and for this a linear model is assumed in the relevant concentration range. Species sensitivities are assumed to follow a non-linear curve (the SSD), relating the exposure to the fraction of species affected, with a maximum of 100% of the species affected.

Medical impact of chemical weapons Exposure to mustards is associated with development of chronic health problems including chronic neurophathic pain [14] increased susceptibility to cancers [15-21] possible defective spermatogenesis [22] ocular injury [23-29] skin lesions [30-34] and respiratory disease [35-45]. During our war with Iraq, reports from Iranian combat aid stations, field hospitals in battle zones and reports by civil authorities, where non-combatants had endured chemical warfare (CW) exposure, more then 100,000 military and civilian personnel had received treatment for acute effects of CW agents [46]. 

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