Atrazine Debate Intensifies

It’s been one year since the Environmental Protection Agency decided to reevaluate the toxicity of atrazine, one of the most commonly used herbicides in the U.S. The agency’s review was expected to be nearly complete by now, but a plethora of new and contradictory studies on the health effects of atrazine have bogged down the process.

EPA assessed the risks of atrazine in 2006 and determined that the 50-year-old weed-killing chemical is safe for use on corn, sorghum, and other crops when applied as directed. Last year, however, the agency decided to take another look at the herbicide because of a handful of studies showing an association between atrazine exposure and birth defects, premature births, and low birth weight in humans (C&EN, Oct. 12, 2009, page 36).

The agency now acknowledges that the quality of those human epidemiology studies is insufficient for use in a quantitative risk assessment of atrazine. Nonetheless, EPA plans to continue with the reevaluation and use the studies qualitatively to provide information on the relevance of animal toxicology findings to human health.

The goal of the reevaluation is to determine whether EPA’s risk assessment for atrazine should be revised, according to Anna Lowit, a health effects scientist in EPA’s pesticide office. EPA also wants to determine whether the frequency of drinking-water monitoring is adequate to assess atrazine exposure, Lowit noted at a Sept. 14 meeting of EPA’s pesticide scientific advisory panel.

Last month’s meeting was the panel’s third meeting this year on the health effects of atrazine. In February, the panel debated ways to incorporate human epidemiology and poisoning-incident data into EPA’s risk assessment of atrazine (C&EN, March 1, page 31), and in April, the group examined the endocrine-disrupting effects of atrazine in various animal toxicology studies. Last month, the panel wrestled with integrating all of the information, including human epidemiology, experimental toxicology, and drinking-water-exposure data.

With respect to human epidemiology, EPA considered hundreds of published studies, but only 19 of them met the agency’s criteria, Carol H. Christensen, an epidemiologist in EPA’s pesticide office, noted at last month’s meeting. To meet the criteria, studies had to measure an association between atrazine exposure and a chronic health effect, as well as measure atrazine exposure specifically. The paper could not be an editorial, and the full text of the paper had to be available, Christensen said.

The studies that made the cut showed associations between atrazine and reproductive effects, including delayed menopause, increased gestational diabetes, and poor semen quality. They also showed birth defects and low birth weight associated with atrazine exposure during pregnancy.

But EPA concluded that these human epidemiology studies are of insufficient quality to include in a quantitative risk assessment. As a result, “EPA will continue to rely on animal toxicology data in quantitative risk assessment,” Christensen said.

The problem is that EPA can’t link atrazine to the reported outcomes. “The lack of an exposure-response measurement for many of these studies, the lack of individual-level exposure measurement, and the lack of validation for use of surrogates for individual exposure” are also factors limiting the use of these studies in quantitative risk assessment, Christensen explained.

Nonetheless, EPA sees some value in the human studies because many of the results are consistent with animal toxicology studies. For example, the reported observation of “small for gestational age” in humans is consistent with the observation of reduced pup weight in animal toxicology studies, Christensen pointed out.

Although EPA has decided to rely on animal toxicology studies, it is unclear how the agency plans to extrapolate results from rats to humans. In addition, the results from one animal study often do not agree with the results from another study. The agency has already examined hundreds of animal toxicology studies on atrazine, including several that were published this year. Some of the papers show reproductive or developmental effects in rats, but others do not.

For example, one study showed delayed mammary gland development in animals exposed to extremely high doses of atrazine (Toxicol. Sci. 2005, 87, 255), and another showed the same effect at low doses (Environ. Health Perspect. 2007, 115, 541). But a paper reporting research funded by Syngenta, the primary manufacturer of atrazine in the U.S., and recently submitted to Toxicological Sciences, found no delay in mammary gland development in rats exposed to atrazine in utero.

One reason for the discrepancies may have to do with differences in when an organism is exposed. Several studies hint at critical windows of exposure, Christensen noted. Researchers at EPA are currently studying hormonal and behavioral changes in rats exposed to atrazine in utero, in the hope of elucidating some of those windows.

In addition to effects on the mammary gland, EPA is particularly interested in understanding the role of atrazine in suppressing the luteinizing hormone. This hormone is produced by the pituitary gland and triggers ovulation in females. Some studies indicate that atrazine exposure suppresses the luteinizing hormone, but others do not.

So far, EPA has identified changes to the neuroendocrine system that lead to reproductive toxicity as the most biologically plausible effects of atrazine exposure. The agency has identified some studies showing atrazine effects on the nervous and immune systems, but these effects were observed only at doses higher than those found to elicit reproductive or developmental effects.

Meanwhile, Syngenta has been conducting its own experiments on the safety of atrazine. The company came to EPA’s advisory panel meeting last month armed with a suite of new research findings, all of which suggest that atrazine is safe.

Syngenta scientists claimed that they have not been able to demonstrate a link between atrazine exposure and a delay in mammary gland development, and they provided evidence that atrazine does not appear to target the pituitary gland or suppress the luteinizing hormone.

In addition, the company presented results from a study showing that a distributed dose of atrazine given to a rat over time produces no effects on reproductive hormones.

Even when extremely high doses of atrazine—up to 500 ppm—were given to rats in a distributed way over time, no effects were observed, stressed Tim Pastoor, principal scientist at Syngenta.

“This highest dose was tens of thousands of times higher than the current EPA water standards for atrazine. People would never be exposed to this level in the environment,” he noted. “Yet even at this extreme dose, atrazine had no effect.” In contrast, when rats were given a large, single dose of atrazine, hormonal effects were observed. Syngenta claims that a distributed dose of atrazine more closely replicates real-world exposure than a single, large dose.

The prospect of a revised risk assessment for atrazine and possible new restrictions on the herbicide has Syngenta, as well as many agriculture groups, worried. Such groups argue that there are no cost-effective alternatives to atrazine, particularly for corn.

A ban on atrazine would lead to $100 million in increased costs annually to Missouri corn growers, Gary Marshall, chief executive officer of the Missouri Corn Growers Association, stressed at last month’s advisory panel meeting. He estimated that in total U.S. corn growers would take a $2.5 billion hit. “Consumers will ultimately pay the higher price,” he said.

The groups are especially concerned about the timing of EPA’s review. They point out that if EPA had followed its normal schedule, atrazine would not have been reviewed until 2013.

“We find ourselves in this very unusual, unplanned re-review of atrazine that deviates considerably from EPA’s long-standing regulatory process,” said Rod Snyder, director of public policy at the National Corn Growers Association. “EPA and the [scientific advisory panel] have already repudiated the very studies EPA relied upon to justify this re-review of atrazine, noting that ‘their overall quality was relatively poor, thus limiting their applicability.’ ”

Just months before EPA launched its reevaluation of atrazine, the environmental group Natural Resources Defense Council released a report showing spikes in atrazine concentrations in drinking water that were well above EPA’s safe level. However, the spikes were seasonal, and the average concentration of atrazine in the drinking water did not exceed legal limits (C&EN, Aug. 31, 2009, page 21).

Atrazine levels in drinking water are monitored weekly from April to August, and the values are averaged over a 90-day period. EPA is concerned that spikes of short duration will be missed by weekly sampling and has asked its pesticide advisory panel for input on selecting the critical duration of exposure. The agency is also proposing more frequent water monitoring and possibly the revision of its exposure calculations to be more protective of infants and children.

EPA plans to follow up the September meeting with another pesticide advisory panel meeting in 2011 to evaluate studies on the potential of atrazine to cause cancer. This should complete the agency’s reevaluation of the herbicide and allow it to make a decision on whether additional restrictions are needed.