Malathion and Cancer: A Pesticide's Risk

Malathion is one of the clearest cases where a hazard body and a regulator reached different conclusions from overlapping evidence. Both conclusions are published, and both can be read in full.

IARC, the cancer agency of the World Health Organization, evaluated malathion in Monographs Volume 112, published in 2017. Its overall evaluation: malathion is probably carcinogenic to humans, Group 2A.

EPA's human health risk assessment for malathion registration review lands elsewhere. Its wording is exact. Malathion is classified as "suggestive evidence of carcinogenicity but not sufficient to assess human carcinogenic potential." That applies by all routes of exposure.

Neither is a mistake. They answer different questions with different rules.

IARC calls malathion a non-systemic, broad-spectrum organophosphate insecticide. It was first sold in the 1950s. It is still made and used in large volumes in many countries.

Its uses run wider than most people expect. IARC lists insect control on crops, pastures, and rangeland. Use in homes and yards. Control of ectoparasites on animals. Pest-eradication programmes. Disease-vector control, such as mosquito spraying. And a drug preparation to treat lice on people.

On exposure, IARC is specific. Occupational exposure has been measured in farm and greenhouse workers, and in pest- and vector-control workers. Dermal contact, meaning skin contact, is the most important route at work.

For everyone else, IARC names three routes. Residues in food. Living near sprayed areas. And home use of products containing malathion. It adds that measured levels in air, water, and soil appear to be low. Urine levels of the breakdown product malathion dicarboxylic acid are generally below 1 µg/g creatinine in the general population.

IARC's evaluation chapter has three findings and a rationale.

On cancer in humans, it found limited evidence. Positive associations were observed with non-Hodgkin lymphoma and with cancer of the prostate.

On cancer in experimental animals, it found sufficient evidence.

Those two together produce Group 2A. Limited human evidence plus sufficient animal evidence is the standard route to that category.

IARC summarizes the epidemiological base for non-Hodgkin lymphoma. The main evidence came from a large pooled analysis of case-control studies with 748 cases, performed in the 1980s in the midwestern United States.

That analysis found a statistically significant link. It tied non-Hodgkin lymphoma to ever being exposed to malathion. The odds ratio was 1.6, with a 95% confidence interval of 1.2 to 2.2.

Two subgroup figures follow. For small lymphocytic leukemia the odds ratio was 1.9, but the confidence interval ran from 0.8 to 4.7, crossing 1. Where exposure had started 20 years earlier or more, the odds ratio was 1.7, with an interval of 1.1 to 2.9.

IARC lists the wider evidence base too. One piece is the Agricultural Health Study cohort. It covered 11 cancer sites in adults, plus childhood cancer. Two more are nested case-control studies. They sit inside the Florida Pest Control Workers cohort and the United Farm Workers of America cohort. Others are case-control studies from the midwestern United States, Canada, Sweden, and Costa Rica.

IARC's rationale says the mechanistic data supported the 2A call. It works through three key characteristics of carcinogens.

First, there is strong evidence that malathion-based pesticides are genotoxic. That means they damage genetic material. The evidence comes from studies in humans, in animals, and in human and animal cells in the lab. IARC notes one exception. Tests for mutation in bacteria came back negative. IARC reads that as no direct pro-mutagenic activity.

Second, there is strong evidence that malathion changes receptor-driven pathways. IARC ties those pathways to tumor findings in hormone-responsive tissues, the thyroid, and the mammary gland. It found matching evidence for altered cell growth in the same tissues.

Third, there is strong evidence that malathion induces oxidative stress and inflammation. IARC says the most extensive data come from live-animal studies. Supporting findings came from human cells in the lab. More came from a study of people acutely poisoned by malathion-based pesticides.

EPA's assessment sets out its reasoning in four numbered points, and they are worth reading rather than paraphrasing loosely.

Liver tumors in male and female B6C3F1 mice were seen only at excessive doses. The same held for female Fischer 344 rats. A few rare tumors did appear in Fischer 344 rats. They were in the oral palate lining in females, and the nasal lining in both sexes. Apart from one nasal and one oral tumor in female rats, EPA judged the rest differently. Those either occurred at excessive doses, or could not be told apart from random occurrence. EPA also states the evidence for mutagenicity does not support a mutagenic concern in carcinogenicity.

That last point is the sharpest disagreement with IARC, which found strong genotoxicity evidence.

EPA's classification is older than it might appear. Its Cancer Assessment Review Committee made the call on 28 April 2000. The rules used were EPA's 1999 Proposed Guidelines for Carcinogen Risk Assessment. EPA notes the wording matches "suggestive evidence of carcinogenic potential" in its 2005 Final Guidelines.

EPA also states that no new carcinogenicity studies in laboratory animals have been submitted since that 2000 evaluation.

But it did revisit the human data. EPA's pesticide programs office ran complete reviews of the available epidemiological data in 2014 and 2016. Those came after IARC's working group met. EPA concluded the epidemiological studies will not likely change its cancer risk assessment. It added that a reevaluation by the committee is not warranted at this time.

So the disagreement is live and documented, not a case of one side being out of date.

EPA's assessment contains a striking figure that is easy to misread.

The body converts malathion into malaoxon. Malaoxon blocks an enzyme called acetylcholinesterase more strongly than malathion does. EPA calculated a toxicity adjustment factor of 22. That means malaoxon is estimated to be 22 times more toxic than malathion.

That figure describes nerve-related toxicity, not cancer risk. It belongs to the acute poisoning side of the assessment.

The cancer most consistently linked in the human studies is described in lymphoma. A closely parallel dispute over another pesticide is covered in glyphosate and cancer. What a Group 2A label does and does not mean is set out in hazard versus risk.

• IARC Volume 112: malathion evaluation
• IARC Volume 112: malathion data summary
• EPA: malathion risk assessment