A group of researchers has called into question the validity of rodent feeding trials, used in biomedical research and in the regulation of commercial products, by analyzing the diets of control rats. The researchers found traces of pesticides, heavy metals and other chemicals in rat feed, and argue that these, along with the genetically engineered crops used in the feed, could be behind the development of cancers in control rats, thereby invalidating the feeding trials. The research, published in PLOS ONE, was from the lab of Gilles-Éric Séralini.
Dr. Carl Winter, Cooperative Extension Food Toxicologist, University of California, Davis (webpage):
Expertise: detection of pesticides and naturally-occurring toxins in foods, how to assess their risks and identify how to use the science in the regulatory decision-making process.
“I find the discussion of data presented in Table 2 to be misleading. The authors contend that since the maximum dietary intake of the pesticide pirimiphos-methyl in seven of the diets exceeds the Acceptable Daily Intake, that animals fed such diets are being fed toxic levels of pirimiphos-methyl. This conclusion is not supported for two reasons:
1) The maximum dietary intake represents an exaggeration of the true dietary intake.
2) (More important) Comparing maximum dietary intake with the Acceptable Daily Intake is not appropriate to demonstrate risk. A more appropriate comparison would be the No Observed Effect Level (NOEL) from long-term animal toxicology studies, which represents the maximum amount given to laboratory animals on a daily basis that does NOT cause any noticeable toxicity. In the case of pirimiphos-methyl, the lowest NOEL I was able to find was from long-term rat feeding studies, which represented a level of 500 micrograms of pirimiphos-methyl per kilogram of body weight per day (http://www.epa.gov/iris/subst/0257.htm). Even the exaggerated maximum dietary intake levels are well below the rat NOEL level.
“ADI levels represent levels considered to be safe for daily human consumption. Calculation of ADI levels typically takes the lowest NOEL found from animal studies and applies uncertainty factors that typically include a 10-fold factor that assumes humans are 10 times more sensitive than the most sensitive animal species studied which is multiplied by another 10-fold factor assuming some humans are 10 times more sensitive than other humans. Thus, a typical uncertainty factor is 100, so the ADI is often the NOEL divided by 100. See this manuscript I wrote that discusses this in more detail. Since the PLOS One study specifically considers the impacts of exposure to chemicals to laboratory animals, there is no need to apply the uncertainty factor.
“For all of the other seven pesticides detected, exposure at the exaggerated maximum dietary intake level was still below the ADI levels, (commonly 100 times lower than NOEL levels from animal studies), so it is difficult to make a valid case as to how such exposures would cause effects in the animals consuming feed containing pesticide residues. It should also be pointed out that these were the only pesticides detected out of 262 analyzed.
“The process of comparing maximum dietary intake levels with ADI levels for other contaminants such as metals and PCDDs and PCBs is similarly misleading.”
Dr. Frédéric Y. Bois, Professor at Sorbonne UTC, and Research Director at L’Institut National de l’Environnement Industriel et des Risques (INERIS)(webpage):
Expertise: pharmacology, quantitative toxicology and risk assessment, with a strong emphasis on mathematical modeling and statistics
“The authors have performed an independent assessment of the contamination of lab rat diets by pesticides, heavy metals and some persistent chemicals. Some producers already check the quality of the diets they produced, according to FDA guidelines for example, but a double check is always good. Not too surprisingly, rat diet, like most of ours by the way, is contaminated with those chemicals. It would actually be interesting to compare those results with the producers’ records.
“Whether the exposed rats are likely to suffer serious damage from such exposures is not clear though. The hazard indexes computed by the authors use acceptable daily intakes (ADI) calculated for humans. Those do not really apply to rats, because safety factors are used in their derivations to specifically protect humans (assumed to be more susceptible than animals), and among humans infants etc.
“Furthermore the hazard indexes for various chemicals were summed to get an estimate of the effect of the multiple exposures. However, this is a very crude method: for example, take three chemicals that have indexes at 0.5 (no problem for them: the exposure level only half of the ADI). If you sum the indexes for those three chemicals you find a global index of 1.5 and we have a problem. But that makes sense only if the chemicals act without thresholds and on the same target, which are all assumptions.
“Using hazard indexes and summing them maybe a reasonable conservative procedure for protecting human public health. However, when assessing the actual impact of food contaminants on the health of lab animals (which is a matter of scientific precision, not of rat health protection) they are likely to overestimate the risks. Animal specific ADIs should be used.
“As to estimating precisely the effect of mixtures of chemicals, this is a hot and debated topic in food safety (the European Union has recently given the green light to a large project, EuroMix on that topic) but we do not have yet good tools to do it precisely.
“Given that, it goes very far to say that most rat feeding studies are flawed or that ‘historical control data’ are unreliable. In the case of low quality diets, some studies may have overestimated the “natural” disease background in the animals. The question is a good one, but should be answered with a more in-depth analysis of the actual risks for those animals.
“The question also of the number of chemicals whose safety evaluation has been biased by the presence of food contaminants in lab animal diets needs to be addressed with precaution, without jumping too fast to conclusions. At least the authors should be congratulated for tackling an interesting question, which, by the way, also extends to the analysis of epidemiological cohorts. In essence, what is a control group? The question again is welcome.”
Dr. Richard E. Goodman, Research Professor in the Food Allergy Research and Resource Program, University of Nebraska (webpage):
Expertise: Refining methods and evaluation criteria for assessing the potential allergenicity of proteins in genetically engineered crops
“Séralini and colleagues have submitted an analytical study reporting on detection of traces of 262 pesticides, 4 heavy metals, 17 dioxins and furans, 18 PCBs and 22 GMOs in a small sample (13) of commercially prepared laboratory animal chow (diets) produced by a number of manufacturers. The study is being reported in the open access journal PloS ONE, that has a generally favorable reputation. But of course even the highest quality journals sometimes publish papers that report sensational findings, yet with little critical review and a lack of connectivity to biological outcomes, as appears to be the case in this study.
“The authors are using a controversial method of estimating cumulative risks (Hazard Quotients) of minor contaminants in animal feeds that have not been validated to demonstrate realistic risks, with biological proof of harm at levels of contamination that the authors found in this PLoS ONE study. As far as I know, there have not been publications demonstrating that the method of cumulative hazard assessment, even though referenced by a paper by the US EPA and one in the EFSA Journal (11:3313), have suggested this approach might be useful for understanding risks of mixtures of chemical toxicants including pesticides, dioxins and heavy metals have accurately predicted risks or outcomes.
“The fact is that no studies I am aware of, other than the authors’ previous retracted study in Food and Chemical Toxicology in 2012 on NK603 maize and glyphosate, has shown high levels of tumors, cancers or other deleterious effects in control animals fed normal commercial rodent diets. The authors have not cited published studies that have shown high levels of adverse effects in control animals fed commercial rodent diets. I have been involved in monitoring rodent studies and in conducting studies of 60 and 90 days in rats and mice and am aware of many studies that are longer that have not shown anything other than occasional adverse effects in control animals that are not associated with an unintended genetic or infectious trait carried in the test animals, and those are sporadic issues that provide some of the background that the authors cite as issues.
“It is quite disturbing to me as a scientist involved in food safety evaluations of GMOs and novel food ingredients as well as all kinds of processed foods that the authors of this study are implying that food raw materials deemed acceptable and without evidence of risks for humans by scientists and regulators in the US, EU, Japan, Australia and a number of other countries are being touted as risk factors for rodents consuming those approved GM events in any toxicology study.
“All agricultural crops, including organically grown crops are ‘contaminated’ with at least low levels of metals, such as arsenic; with some level of chemical herbicide or insecticide and other compounds. If those compounds are fed at high concentrations to animals or humans there would likely be some adverse effects. Drinking too much water in a day (~ 4 gallons) will lead to death in a typical human. Consumption of too many calories over time will increase the rate of developing certain types of tumors or cancers. Consumption of some vitamins at a high dose over time will cause adverse health effects. The authors report detection in the range of parts per billion of a number of compounds that are deemed safe by regulators at the levels found in the rodent diets.
“It seems the authors are trying to prove that their earlier reported tests with high tumor incidence in the 2012 study was due to “incidental contamination of control diets” rather than the genetic strain of rats used in their 2 year study. Or that they want to invalidate the safety tests on many GM crops. Yet the same tests and lab chow has been used safely to demonstrate convincing risk or safety of a number of pharmaceuticals, pesticides and other compounds.
“While their data is superficially interesting, the value really is to show that all food and feed contains small amounts of chemicals and metals, and that we should not be afraid to consume commodity crops that are grown with a wide variety of methods of cultivation, by farmers who follow appropriate guidelines for the use of chemicals. Even organic farmers use some metals legally, and many non-organic farmers use chemicals that allow the safe and efficient production of food and feed and if they follow labeled approved dose schemes, the residues of pesticides on the food materials will be far below hazardous levels.
“If we allowed the data of these authors to scare us from using the animal safety testing methods we have used for decades, or if we allow them to “invalidate” years of testing, we will not be able to make safe decisions about our food, our pharmaceutical products or even drinking water. As with the 2012 study, the authors have chosen to put out press releases and announce their findings in controversial and alarming terms, this time before the public release of the study by the journal. I hope the sensationalistic press conferences and hype used by the authors go out of vogue. They do not help the public or regulators decide what is safe and what is not safe.”
‘Laboratory Rodent Diets Contain Toxic Levels of Environmental Contaminants: Implications for Regulatory Tests’ by Séralini et al, published in PLOS ONE on Thursday July 1, 2015.
Declared interests (see GENeS register of interests policy):
Dr. Richard Goodman: Prior to my current position I worked at Monsanto from 1997-2004 on the safety evaluation of genetically modified crops (GMOs), primarily evaluating potential allergenicity, also potential transfer of DNA from GMOs to other organisms including gut microbes and livestock and to some extent on the potential toxicity of GMOs.
I am paid by the University of Nebraska from grant money and contracts that I perform for a variety of companies, governments and non-profit organizations. I do not receive any money from companies to defend their products.
I served as an Associate Editor for the journal Food and Chemical Toxicology from late 2012 until March, 2015. That was just after publication of a paper by Séralini describing the 2 year rat feeding study which reportedly showed tumor incidence in rats fed herbicide tolerant maize (NK603), or with glyphosate in the water, or a combination of both. After a year review, which I was not involved in, the journal (FCT) withdrew that paper.
No further interests declared