Safe dose levels, chemical risk assessment

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 faaor 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-... 

For nongenotoxic chemicals, risk assessment is based on the concept of threshold doses, below which no adverse effect results from exposure. From human or experimental animal data, one tries to establish the no observable adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL). In order to establish safe levels of exposure to potentially toxic agents, the NOAEL is divided by a safety factor (often named uncertainty factor). When the risk assessment is based on data from experimental animals, a default safety factor of 100 is usually applied. The safety factor constitutes a factor of 10 for potential differences in susceptibility between animals and man, and another factor of 10 for interindividual differences among humans. The factors are combinations of differences in toxicokinetics and toxicodynamics, both in animals and man. If true factors are known, the size of the safety factor may be changed accordingly. When risk assessment is based on human data, a safety factor of 10 is applied in most cases, for instance, for food additives. However, for natural toxins in food, smaller factors are usually applied. This is a risk management decision, often based on information on the absence of adverse health effects at intake levels close to the estimated LOAELs. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-4 shows a conceptualized representation of a PBPK model. 

In 1958, in response to the increased awareness that chemicals can cause cancer, the US Congress passed the Delaney clause, which prohibited the addition to the food supply of any substance known to cause cancer in animals or humans. Compared with today s standards, the analytical methods to detect a potentially harmful substance were very poor. As the analytical methods improved, it became apparent that the food supply had low levels of substances that were known to cause cancer in either animals or humans. The obvious question was Is a small amount of a substance safe to consume. This question in turn raised many others about how to interpret data or extrapolate data to very low doses. The 1970s saw a flourishing of activity to develop and refine risk assessment methodologies. 

This means that extrapolating from a high dose of a chemical to a very low dose to determine a threshold and calculate risk may not be appropriate (see Chapter 12), especially if a linear model is used which implies there is no safe dose (for example, for a carcinogen). If true this has profound implications for risk assessment, suggesting that we may sometimes have been more cautious than necessary Thus attempting to reduce exposure levels for chemicals excessively may be unnecessary and, worse, a waste of effort and money. 

Long-term animal studies of dermal exposure to crude oil can be used to set a no observed adverse effect level (NOAEL) that can be used to predict safe human exposure levels for both dermal and systemic effects. A reference dose of 0.04 mg kg day has been suggested for exposures to crude oil. The individual aliphatic and aromatic fractions of crude oil have also been evaluated for toxicity and sufficient information exists to set references doses for these fractions. An understanding of the exposure to the individual fractions is necessary to use this process. The use of the reference dose for either crude oil as a whole or the individual fractions is preferable to evaluating only the toxic constituents in crude oil. This latter strategy is commonly employed in risk assessment however it ignores the hydrocarbon matrix within which these toxic chemicals are found. This hydrocarbon matrix affects the exposure to... 

OEHHA (2008). Proposition 65 Safe Harbor Levels No significant risk levels for carcinogens and maximum allowable dose levels for chemicals causing reproductive toxicity. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA. Accessed at http //www.oehha.ca.gOv/prop65/pdf/Feb2008StatusReport.pdf. 

Now I hope you see why I believe that it is criminal to sound an alarm when a pesticide residue is detected on produce at 100 to 1000 times below the tolerance. The tolerance is related to a safety threshold, not a toxic one. This misuse of data totally ignores the entire risk assessment process that is appropriately conservative and protective of human health. What is even more ironic is that the very chemicals that the public is made to fear in food at these below-tolerance levels are often used by the same individuals in household and garden pesticide products at much higher doses. These are generally proved to be safe for most individuals, making worrying about food concentrations millions of times lower a totally worthless experience that detracts us from more serious concerns. 

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