Garbage in, garbage out

Throughout the 1970s, EPA staff repeatedly raised red flags about the inadequacy of testing data that Monsanto was submitting in support of glyphosate’s original registration. For example, in an August 1978 memo, TB scientist Krystyna Locke raised concerns about a Monsanto study in which the scientists from the contract lab had failed to record what happened in the experiment. Locke quoted Monsanto scientist Robert Roudabush, who defended the study this way: “The scientific integrity of a study should not be doubted because of the inability to observe all primary recording of data.” In other words, the EPA should not be concerned by the absence of data. It should simply trust the study’s conclusions.

The EPA’s Locke also pointed out that it is “difficult not to doubt the scientific integrity of a study when the [lab] stated that it took specimens from the uteri (of male rabbits).” (A male rabbit does not have a uterus.)

This is only the most egregious example of the unreliable data made available to the EPA during its original regulatory review in the 1970s. Many other EPA memos we examined detail incomplete or otherwise unacceptable toxicology screening tests.

Conversely, one apparently valid study has been the target of major attempts to discredit it by both EPA management and Big Ag. In 1983, the EPA was continuing to examine glyphosate toxicity data supplied by Monsanto in anticipation of the registration review that the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) requires for each pesticide at least every 15 years. As part of that process, Monsanto submitted to the EPA a two-year mouse feeding study—a study that has since become a thorn in Monsanto’s side and a drag on the EPA’s push to find glyphosate benign. Its history merits close scrutiny.

The mouse study was conducted for Monsanto by a commercial lab called Bio/Dynamics, but the results of the research were neither peer-reviewed nor made publicly available. Bio/Dynamics studied 200 mice: 50 unexposed control mice and three groups of 50 mice exposed to three different doses of glyphosate. Four of the exposed mice—one at the middle dose and three at the highest dose—developed kidney tumors called adenomas, which tend to be initially benign but can transform into cancers.

Staff toxicologists, pathologists and statisticians in the TB provided the first interpretation of these results. On March 4, 1985, an ad hoc committee of these scientists reported that based on this mouse study, glyphosate was carcinogenic, or a “Class C” substance. They did not question the 1983 study’s structure or reported data. EPA staff toxicologist William Dykstra, in an April 3, 1985, memo, stated unequivocally, “Glyphosate was oncogenic in male mice causing renal tubule adenomas, a rare tumor, in a dose-related manner.”

Outside experts

The TB scientists recommended further expert analysis, so in the fall of 1985 Monsanto recruited four outside pathologists to review the original tissue slides from the 1983 study and—eventually—fresh slides taken from the same animals used in that original study. In a March 11, 1986, memo, Dykstra reported on the results of this review: One of the outside pathologists, Marvin Kuschner, saw a tumor in the control group of mice like those found in the exposed groups. Based on this finding, the EPA decided to discount the entire study on the grounds that if an unexposed control mouse had a tumor, the tumors in the exposed mice were “not compound-related.” Subsequent evaluation of the same evidence by other pathologists found no evidence of a tumor in the control mouse, but the seeds of doubt had already been sown. As late as 2016 the EPA still mentioned the tumor in the control mouse, although it was not there.

Dissatisfied with the first outside experts’ verdict, the EPA asked another five outside pathologists to look at the mouse tissue slides from that study. According to a March 1, 1986, memo from EPA Hazard Evaluation Division toxicologist D. Stephen Saunders, these experts decided that “the incidences of renal tubular-cell neoplasms in this study are not compound-related”—in other words, that the kidney tumors were not related to glyphosate exposure.

Throughout this process, the EPA was riddled with internal dissent. In February 1985, TB statistician Herbert Lacayo wrote an impassioned memo regarding the 1983 mouse study. He concluded that without glyphosate exposure, the odds of seeing the kidney tumors noted in the study were about 156 to 1.

“Under such circumstances a prudent person would reject the Monsanto assumption that glyphosate dosing has no effect on kidney tumor production,” wrote Lacayo. “Our viewpoint is one of protecting the public health when we see suspicious data. It is not our job to protect registrants from false positives.”

PassÉ Toxicology

Monsanto’s interests were protected by a toxicological tenet that held sway at the time: the linear dose-response. This assumes that the greater the dose of a toxic substance, the greater the effects, and vice versa, often phrased as “the dose makes the poison.” Under this assumption, a carcinogenicity test would be expected to show tumor size or tumor numbers increasing in linear relation to increased exposure to the carcinogen. In the mouse study, tumor numbers followed this pattern, which the TB noted was an indication that the tumors were glyphosate-related. But the largest tumor was found in one of the middle-dose mice. Pathologist Robert A. Squire, a member of the first outside group consulted, wrote in a September 1985 letter to Monsanto, “This would be highly unlikely if the tumors were compound-related.” Thus, even though the tumor numbers followed a linear dose-response, the tumor size of the middle-dose mouse presented an opportunity to discount glyphosate’s effects as non-linear and therefore nonexistent.

In some circumstances, the linear dose-response reasoning makes sense, but the science of chemical health effects has advanced considerably since the 1980s. It is now generally accepted among academic researchers that non-linear dose-responses—responses in which low levels of exposure may produce more significant effects than high levels and responses in which effects at high doses sometimes plateau or tail off—often occur.

None of the regulatory studies of glyphosate considers the possibility of non-linear dose-responses. The registration documents submitted by Monsanto show that when glyphosate testing data did not conform to the linear dose-response model, the company’s hired scientists and the EPA’s consultants concluded that adverse effects found in exposed animals were not caused by glyphosate. But this outdated approach underlines why glyphosate’s toxicity should be revisited using modern concepts and methods.

After a decade of EPA staff scientists repeatedly flagging inconsistencies, mistakes and questionable scientific interpretations in Monsanto’s data, one might expect the EPA to require rigorous new studies. Instead, the agency continued to invite outside experts to review the data, as though it was determined to ask the same question until it got the answer it was looking for.

Don’t like the answer? Ask again.

In early 1986, the EPA called in yet more outside experts—namely, the agency’s FIFRA Scientific Advisory Panel. The seven-member panel included the head of biochemical toxicology and pathobiology at the Chemical Industry Institute of Toxicology (CIIT). This institute was founded by chemical manufacturers and funded by organizations and companies that included the American Chemistry Council (an industry group that boasts Monsanto as a member), and pesticide manufacturers BASF, Bayer and Dow Chemical. The panel also included a consultant who had worked for the ChemAgro Corporation (later part of Bayer’s agricultural division) before founding her own consultancy.

The FIFRA panel felt that calling glyphosate carcinogenic was going too far and suggested downgrading its classification to D, “not classified.”

Biostatistician Christopher Portier, formerly a director of the Agency for Toxic Substances and Disease Registry (part of the Department of Health and Human Services) says the agency should have stuck with the TB ad hoc committee’s original interpretation. Of the FIFRA panel, he says, “I have no clue how they got there.”

At the same time, according to a February 1985 summary memo by Stephen L. Saunders, based on the panel’s advice, “The Agency has determined that the existing mouse study does not provide sufficient evidence for a resolution of this issue. Therefore, a repeat mouse study is required.”

Despite the EPA’s requests for a clarifying experiment, Monsanto apparently refused. Monsanto’s registration director George B. Fuller protested vigorously in an Oct. 5, 1988, letter to the director of the EPA’s Office of Pesticide Programs, Edwin F. Tinsworth. “[There is] no relevant scientific or regulatory justification for repeating the glyphosate mouse oncogenicity study,” Fuller wrote. “We feel that to do so would not be an appropriate use of either the Agency’s or Monsanto’s resources.” In a 1988 meeting, the company again pressed the EPA to give up on the repeat mouse study requirement. The EPA backed down.

To our knowledge, the original 1983 mouse-feeding carcinogenicity study was never repeated.

What is clear from available EPA internal records is that when test results suggest toxicity, EPA management—as opposed to EPA staff scientists—consistently gives Monsanto and its testing laboratories the benefit of the doubt. They defer to Monsanto’s preferred conclusions instead of requiring the development of additional evidence that would clarify the questions regarding glyphosate’s carcinogenicity. The documents we have examined indicate that the EPA may have asked for—or intended to enforce a requirement for—better data, but we have seen nothing to show that the agency ever did so. The EPA did not respond to our request for comment.

Despite these omissions and questions, in June 1991, the EPA announced that it was downgrading glyphosate from a “Class D”—“not classifiable” substance—to a “Class E” substance—“one that shows evidence of non-carcinogenicity for humans—based on the lack of convincing evidence in adequate studies.” (Note that this implies adequate studies might still provide convincing evidence.)

IARC awakens regulators

After the EPA reregistered glyphosate in 1993, the agency’s investigation of glyphosate’s potential health effects became more or less dormant until controversy erupted when the World Health Organization’s IARC concluded in 2015 that glyphosate was “probably carcinogenic to humans.” That in turn prompted the EPA to develop its Fall 2016 “Glyphosate Issue Paper.” This document references the 1983 mouse study as a linchpin in its conclusion that glyphosate is not a human carcinogen. Referring to the 1983 study, the EPA wrote, “The additional pathological and statistical evaluations concluded that the renal tumors in male mice were not compound-related.”

For its part, Monsanto called the IARC review “flawed” and accused the IARC committee of cherry-picking and overlooking data. Monsanto demanded the report’s retraction.