Monday, December 31, 2012

Extrapolating Radiation Effects: The Problems With Laboratory Research

Efforts to predict the toxic genomic effects of chemicals and radiation typically involve one or both of the following extrapolations:

1. Effects for humans are extrapolated from effects on animals studied in labs

2. Low dose effects are extrapolated from high dose effects in lab animals. As Gary E. Marchant notes in his chapter on Toxicgenomics and Environmental regulation: "risk assessors have had to rely on models to extrapolate results from high to low dose levels." p. 12

Each of these extrapolations poses problems. 

For example, Marchant notes that "A finding that gene expression changes characteristic of the carcinogenic response of a particular agent at high doses are also observed in low-dose groups, even though those low-dose animals may not develop tumors, may indicate that low-dose exposures present a carcinogenic risk in large populations" p. 12

Let me translate what Marchant is saying and its implications for government approval of chemicals:

Imagine a company testing whether its chemical is carcinogenic. The lab tests reveal that at high doses tumors develop. These tumors are CLINICALLY EVIDENT.

However, the lab tests reveal that there were no statistically significant developments of tumors at lower doses in the lab animals.

So, the company tells the EPA that its lab results indicate a THRESHOLD under which no statistically significant evidence exists of tumor development. The EPA approves the chemical figuring that most populations will have exposure levels below the level of significance for tumor threshold.

However, the test results may be misleading because genetic and epigenetic changes may have occurred (but were not investigated) that will either 

1.) cause tumors to develop in a small (vulnerable) subset of the population and/or

2.) cause tumors to develop years later as a result of small changes in gene expression.

Consequently, the EPA may inadvertently approve for use a chemical that 1.) causes tumors in a genetically vulnerable subset of the population and/or 2.) causes tumors over long periods of time due to either subtle genetic or epigenetic changes.

Now let us consider for a moment the problem of extrapolating from lab animals.

Lab animals live in carefully controlled environments. Therefore, their overall exposure to toxicgenomic insults may be lower than the exposure levels of animals (including humans) living in the world.

So, animals living in the world likely have more exposure to other chemicals and radiation, increasing their susceptibility to each additional insult. Microwaves, cigarette smoke, Round-Up are examples of commonly found carcinogens in our environment.

The overall body burdens of animals in the world may be much greater than the overall body burdens of lab animals, making them more vulnerable to each additional insult.

Relatedly, humans and other animals in the world are born with genetic damage and their overall levels of inherited damage may be greater than those found in lab animals raised for generations in carefully controlled environments.

Damage to germ line cells is inherited so that each generation inherits the genetic and epigenetic damage to germ line cells from their parents. I therefore have the genetic damage from both my parents. My kids have damage from my germ line cells and from their father's germ line cells.

My kids may be born genetically vulnerable because of parents were, for example, small children during the period of atmospheric hydrogen bomb testing and happened to live in areas subject to high levels of fallout.

So, the laboratory tests of animals may lack ECOLOGICAL VALIDITY because those animals carefully selected environments do not represent the real world conditions humans and other animals in the world are routinely exposed to.

1 comment:

  1. Excellent post, and a very important point! Vast implications.