Toxicity, Risks, and Risk Assessment

Earlier in this chapter, a short introduction to risk assessment and the concept of risk was given (see section 5.3.1.5). In this context, the same issues will not be re­peated. However, the risk assessment concepts and methodologies will be dis­cussed in more depth after the reader has received more insight into the role of toxicology in risk assessment, and after many of the principles of risk assessment, such as dose-effect and dose-response relationship, have been clarified. It is still worth emphasizing that the concept of risk is utilized to indicate hazards in the traffic, sports, health care, and even in the monetary markets, not to mention in relation to alternatives of energy production, e. g., nuclear power and its utiliza­tion. Toxicology has taken advantage of the concept of risk because it so neatly crystallizes the key issues of toxicology, prevention of chemical and other health hazards, and guaranteeing safety to humans.49’129’180

The term risk implies the probability that a certain deleterious health effect will take place under defined circumstances. Likewise, the term security implies the probability that no such deleterious incident will take place under defined circumstances. This kind of definition of risk or security has its foundation in an experimental setting. However, humans or wild animals do not live under de­fined conditions, but rather face a variety of challenges each day. T herefore, reli­able risk assessment is an extremely difficult and tedious undertaking. One of the most challenging issues of toxicology has been assessment of carcinogenic risks induced by chemicals. In the first phase, we shall assess, on the basis of weight of evidence, whether a chemical is a carcinogen or not. This estimation is followed by another, even more demanding task with the goal of estimating the magnitude of the risk of humans exposed to a given chemical in an occupational setting or in their general environment. The outcome of such an assessment should be an estimate of the actual number of additional cases of cancer among exposed persons. This risk assessment utilizes data from experimental animal studies, epidemiological human studies, and all available information on human exposure under different occupational and other living conditions.49

Toxicity, Risks, and Risk Assessment

TABLE 5.23 Biomonitoring Serves Three Different Purposes of Identifying and Using

1. Biomarkers for susceptibility of an individual within a population of

One species to exposure to an intoxicant—genetically determined susceptibility.

2. Biomarkers for internal dose oi the intoxicant—dose monitoring.

3. Biomarkers for early biological changes following exposure— effect

Monitoring.

Source: Modified from Aldridge.64

2. Hazard characterization and delineation of dose-effect or dose — response relationships

3. Assessment of exposure

4. Risk characterization

Risk characterization should preferentially include qualitative and, if pos­sible, also quantitative risk assessment based on steps 1-3.

Hazard identification, step one, means identification of new chemicals or other factors that may cause harmful health effects. Previously, novel hazards were usually observed in case studies or after accidents or other excessive exposures, usually in occupational environments. Today, thor­ough toxicity studies are required on all pesticides, food additives, and drugs. New chemicals also have to be studied for their potential toxic ef­fects. Thus, earlier hazards were in most cases identified after they had caused harmful effects in humans. Today, most chemical products have been evaluated for their toxicity with experimental animals. Therefore, hazard identification has become a preventive procedure based on safety studies conducted before a chemical compound or product reaches the market, and before individuals are exposed to it.49

Hazard characterization, step two, usually utilizes data from toxicity studies with experimental animals. In step one, compounds that have to be studied for their toxicity were briefly described. Health authorities in different countries have issued strict guidelines and regulations on the studies that have to be carried out to evaluate the toxicity of pesticides, food additives, and drugs. Furthermore, the European Union and the OECD have issued regula­tions that are followed in these countries. For example, in the United States, the U. S. Environmental Protection Agency and Food and Drug Administration carefully control the safety of drugs, food additives, pesticides, and other chemicals. The technical quality of the studies has been regulated in detail by good laboratory practice (GLP) guidelines. In Table 5.24, the toxicity/safety studies utilizing experimental animals or other test systems required for the registration of drugs, pesticides, and food additives have been listed.49

Exposure assessment, step three, allows a risk assessor to estimate the sig­nificance of the effects induced by high doses of a chemical in experimental animals in a human situation. Exposure assessment is, in fact, a prerequisite for quantitative risk assessment because it allows a comparison between ef­fects induced by high dose with those induced by low doses, and also allows

TABLE 5.24 Toxicity Studies for Safety Evaluation of Drugs, Pesticides, Food Additives, and Other Chemicals Utilizing Experimental Animals and Other Systems Required by Health Authorities

Name of study

Animal species

Duration of study

Reason for study

Biotranstormation

Rats/mice

One day to weeks

Metabolism

Ksnetic studies

Rats/mice

One day to weeks

Absorption, distribution, and elimination

Acute toxicity

Rats/mice

2 weeks

Acute effects

Subacute toxicity

Rats/mice

2-3 weeks

Delayed effects, target organs

Subchronic study

Rats/mice/dogs/rabbits

6 months

Target organs, delayed effects

Chronic studies

Rats/mice

1 8—24 months

Chronic effects of low exposures

Carcinogenicity

Rats/micr

18-24 months

Carcinogenic potential

Teratogenicity

Rats/rabbits

3-4 weeks

Teratogenic potential

Reprod uctive

Rats/mice/rabbits

Several months

Potential to affect

Toxicity

Reproduction

Irritation

Rats/rabbits

Few days

Irritation index

Sensitization

Guinea pigs/rars

Few weeks

Potential to sensitize

Muragenicuy,

Rats, mice, bacterial

Few days

Potential to cause mutations,

Genotoxicity

Strains, yeasts

Chromosomal damage, and other genotoxic effects

One to compare a dose that causes a toxic effect in an experimental animal with the human dose in an occupational setting or general environment. This is vital because, in most cases, assessment of toxicity, e. g., hazards of new chemicals, is based purely on experimental animal studies. Assessment of ex­posure in the occupational environment relates the human situation to the toxicity data derived from experimental animal studies.

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety-margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e. g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e. g., safety factor of

4 for biotransformation and 2.5 for sensitivity; 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i. e., the no-ob- servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occa­sionally, a NOAEL is not found, and one has to use the lowest-observable-adverse — effect level (LOAEL) in safety assessment. In this situation, often an additional un-

Toxicity, Risks, and Risk Assessment

FIGURE 5.56 The "threshold region" for chronic dose-response curves.49 [Reprinted with per­mission from Tardiff, R. G., and Rodricks, J. V. (1987). (Eds.), Toxic Substances and Human Risks: Principles of Data Interpretation. New York: Plenum Press.]

Certainly factor is added, and then the dose is divided by a factor of 1000. A similar approach is also used when one deals with an exceptionally serious toxicological end point, such as epigenetic carcinogenesis or malformations, which has a threshold dose. This kind of approach is utilized when one deals with deterministic toxicologi­cal effects, e. g., target organ toxicity (neurotoxicity, kidney toxicity). This approach also requires the assumption of a threshold for the effect, i. e., that there is a safe dose below which no harmful effects occur Typically, this approach assumes that a chem­ical compound expresses a typical sigmoidal dose-effect curve in its toxic effects (see Fig. 5.56).49

When one has to assess risks of compounds with carcinogenic or allergic properties, risk assessment becomes much more difficult. This applies espe­cially to genotoxic carcinogens, which have been assumed not to have a safe level; the only safe level would be zero. In this circumstance, linear extrapola­tion (straight line from LOAEL to zero) or various mathematical models that assume the absence of a safe dose have been utilized in human risk assessment, In these instances, the acceptable risk level has been set to 1/1000000. It has to be kept in mind that linear extrapolation or mathematical models are being used because the true mechanisms of chemical carcinogenesis are not known. Therefore, risk regulators, when carrying out risk assessment, are conservative in their risk assessment to guarantee safety of exposed populations. This does not mean, however, that the approach is correct.49’180-201’202 Figure 5.57 indi­cates the differences in risk estimates that can be obtained from the same set of data utilizing different mathematical models.49

Recently it has been argued that genotoxic carcinogens may also have a threshold in their carcinogenic effect. If this assumption were to be accepted by the regulators, it would have a tremendous impact on risk assessment throughout the world. It would mean that safety factors would also be used when determining safe dose levels for genotoxic carcinogens, and this would affect most of the regulatory limits set for chemicals.

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