STATS at George Mason University how to evaluate health risks
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3. What was the dosage?

Check box When you look at health research and risk determinations, check the dosage given to the subjects and the other related variables to be sure it’s comparable to the kind of exposure you may have or be considering and weigh human data more heavily than animal research.

check box Remember that even the most benign substances can become toxic when administered in high doses.

check box The number of exposures, the actual dose in each exposure, the timing of the doses, the time between them and the length of time exposed in total — all of these matter.

 

Many studies examining the risk to humans from chemicals do so by testing the chemical on animals or animal organ cells (in utero) in a laboratory and then extrapolating to lower doses for humans. There are good reasons for this approach, not least that experimenting with potentially toxic chemicals on humans would be unethical. And there are many benefits: for instance, scientists first discovered that penicillin was an effective drug through testing it on mice.

But it is important to be aware of the limitations of animal testing

First of all, everything is toxic if ingested in large enough quantities. This easily-overlooked truth was first enunciated by the Swiss thinker Paracelsus in the 16th century, when he observed that the difference between a poison and a remedy is the dose.

As the British biochemical toxicologist John Timbrell notes in his recent book ‘The Poison Paradox,’ “This is a fundamental concept which underlies toxicology and is crucial to the assessment of risk from chemicals and their safe use. The corollary to this principle is that all chemicals are potentially safe at some, perhaps extremely low, dose and therefore can be used safely.”

As Timbrell explains, in order for a chemical to produce an effect, toxic or otherwise, it needs to interact with receptors or enzymes in a cell molecule. If the amount of the chemical is insufficient to bind itself to most or all of the receptors in a cell there is no effect. As a consequence, most regulatory bodies that assess the risk from chemicals work on the principle that there is a threshold below which there will be no effect. This is known as the “no observed adverse effect level” (NOAEL). Regulatory bodies then create exposure guidelines that add a margin of safety 100 to 1000 times lower than the NOAEL.

The upshot is that it is simply wrong to assume that the risk from a “toxic” chemical is always linear — meaning that it decreases as exposure to the chemical decreases, but never disappears.

There is an important caveat to note here, namely that in the case of chemicals considered to be carcinogenic, some scientists believe there is no threshold below which they are safe: the process of molecular interaction is genotoxic, meaning that the chemical damages the DNA of the cell no matter how low the exposure. The risk, in other words, is linear. The Environmental Protection Agency issues exposure guidelines based on this theory.

It is fair to say that this hyper-cautious approach to risk is controversial for the following reasons: not all carcinogens are genotoxic; there is experimental data which suggests that there are thresholds for genotoxic carcinogens; and more generally, there are barriers that reduce absorption into the body and mechanisms which repair cellular damage. Timbrell illustrates why one shouldn’t assume that exposure to very low doses of a chemical — even one that is a demonstrated carcinogen - is necessarily harmful:

“[S]uppose there is a poisonous chemical, a carcinogen, in a foodstuff. Not all the food will be contaminated, so some individuals will escape exposure. If the food eaten is contaminated, suppose it contains 1mg of carcinogen but only 1 percent is absorbed (0.01mg). Of that 1 percent suppose that only 1 percent is metabolized to the toxic (carcinogenic) substance (0.0001mg). Of that toxic substance, suppose that only 1 percent reaches the target, for example the DNA (0.000001mg). Of the damage caused, suppose that 99 percent is repaired, and that only 1 percent is potentially damaging (effectively 0.00000001mg). This means that only 100 millionths of the original dose reaches the target and causes damage, and damage to DNA does not necessarily result in cancer.”
It is important to understand the basic principles and controversies in toxicology and risk assessment because neither the groups claiming that we are at risk from trace amounts of chemicals nor the media that cover their studies and reports ever seem to acknowledge or address them. Without addressing each potential risk at this level of analysis, scare headlines may convey the idea of a risk to public health that, in effect, might be zero.

Additionally, a growing body of evidence also points to the possibility that small amounts of toxins may be good for you in that they stimulate the cell’s protective mechanisms. This theory — known as hormesis — is still controversial; but if it turns out to be true, much of the research in toxicology will have to be recalibrated.

Another potential problem with animal testing is that physiological differences between species and sexes among animals can create a false sense of risk . Saccharine, for example, was found to cause bladder cancer in male rats at very high doses but not female rats or other species. After further studies, the World Health Organization, the European Union Scientific Committee on Food, and the Food and Drug Administration concluded that the mechanism which produced the tumors did not apply to humans.

Unfortunately, the media usually ignore all these points, with the result that either very small or entirely hypothetical risks to human health continually get headline treatment.

 

assessing cancer risks from chemicals

The Carcinogenic Potency Project at Berkeley University has compiled a ranking of possible carcinogenic hazards from average US human exposures to known rodent carcinogens.

These "analyses are based on the Human Exposure/Rodent Potency index (HERP) which indicates what percentage of the rodent carcinogenic potency (TD 50 in mg/kg/day) a person receives from a given average daily exposure over a lifetime (mg/kg/day)."

A HERP of 0.00001% is approximately equal to a regulatory risk level of 1-in-a-million based on a linear model, i.e. the Virtually Safe Dose (VSD) (Gold et al. , 1992). Naturally-occuring chemicals in food and drink are colored blue.

“Overall, our HERP ranking shows that synthetic pesticide residues rank low in possible carcinogenic hazard compared to many common exposures. HERP values for some historically high exposures in the workplace and some pharmaceuticals rank high, and there is an enormous background of naturally-occurring rodent carcinogens in average consumption of common foods. Results on this background of natural chemicals cast doubt on the relative importance of low-dose exposures to residues of synthetic chemicals such as pesticides”

recommended reading

This is must-read book for journalists and editors covering the health and environmental beats - and a lucid guide for anyone wanting to get a grasp of the basic principles of toxicology, namely

The author, John Timbrell, Professor of Biochemical Toxicology at King's College, London, challenges the widely-held perception that "man-made" chemicals are bad while"natural" ones are safe and shows how scientists assess the risk from environmental contaminants, food additives and industrial chemicals.

"Compelling" - The Lancet

"The author is not a ‘doom and gloom’ merchant. When he deals with the rise and fall of the insecticide DDT he points out that not a single human fatality was associated with its use. On the other hand, the well-meaning banning of this substance has resulted in thousands of deaths — some associated with the toxicities of the organophosphates that replaced it, but mainly from the re-emergence of mosquito-borne malaria that hitherto DDT was effectively controlling" - Royal Society of Chemistry  

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