LONDON – In the spring of 2015, chemical engineer Melvyn Kopstein wrote to the International Agency for Research on Cancer (IARC) to alert it to what he thought were serious flaws in its work. Kopstein believed the agency, a semi-autonomous part of the World Health Organization, had made errors in reviewing benzene. The agency had underplayed human exposure to the carcinogenic chemical, he believed, and it needed to correct matters.

Three years on, he’s still trying to get IARC to address his concerns. In emails seen by Reuters, the agency agreed with Kopstein that its review of benzene had limitations; but an email from one of its senior scientists also said: “We do not plan to amend (it) or take any further action.”

Kopstein, from Maryland in the United States, has decades of experience in analysing evidence on chemicals. He says he was taken aback. “It was totally unexpected,” he said in an interview. “After all, they – IARC – are supposed to be the go-to source around the world of unbiased scientific information on the carcinogenicity of products and chemicals.”

It’s a tale that sheds new light on how the cancer agency operates, and comes at a time when it is facing scrutiny from U.S. lawmakers over its methods and transparency.

Reuters revealed last year how IARC, in reviewing the weedkiller glyphosate, excluded some data and findings that the chemical was not linked to cancer in people: In other words, how the agency may have overplayed evidence of carcinogenicity. In the case of benzene, Kopstein claims IARC did not consider important evidence that exposure to the chemical is higher than IARC suggests: In other words, he argues, the agency may have underplayed potential cancer risks.

The disclosures are significant because they give rare insight into IARC’s methods. The agency does not publish details of how it makes its assessments and forbids observers invited to its meetings from talking publicly about the proceedings.

The Kopstein dispute centres on a report - Monograph 100F - in which IARC classified benzene as able to cause cancer in humans, but said people’s potential exposure to it at work had generally been below recommended daily limits since the 1980s. In Kopstein’s view, the agency failed to properly evaluate the evidence on human exposure to benzene.

Millions of workers around the world – from car mechanics to cabinet makers to shoemakers, print workers and painters – use benzene-containing products such as adhesives, solvents and cleaning agents, sometimes in poorly-ventilated factories or workshops. In the United States, some workers are pursuing personal injury lawsuits claiming serious harm from benzene.

Kopstein has acted as an expert witness for plaintiffs who believe exposure to benzene in products at work made them ill. He says peer-reviewed scientific evidence shows that occupational exposure to benzene can be significantly higher than IARC’s assessment suggests. When he became aware in 2015 of the detail of IARC’s benzene assessment, he wrote to the agency.

In emails spanning several months, reviewed by Reuters, a senior IARC staffer and a scientist involved in IARC’s assessment of benzene told Kopstein that the agency’s evaluation of the chemical did indeed have limitations. Kurt Straif, the head of the IARC “Monograph” unit that assesses the carcinogenicity of substances, said the exposure section of the benzene study was “condensed” due to cost and time constraints, and was not intended to be “exhaustive.”

Martyn Smith, a member of the IARC working group that reviewed benzene and other substances, told Kopstein in an email the review had “tried to cover too much ... so I’m not surprised it has left out key findings or focused on the wrong studies.” Smith did not respond to Reuters requests for comment.

IARC's monographs – scientific reviews that classify human carcinogenic hazards – are cited by governments, courts and regulators worldwide as the reference “bible” of what causes, probably causes, and possibly causes cancer in people. Yet here were IARC insiders telling Kopstein that one of its own reviews was not comprehensive.

Kopstein regards such limitations as a serious flaw because, he says, government regulators, public health officials and others need “balanced and accurate” information from IARC.

“I’m not surprised it has left out key findings or focused on the wrong studies.”

Reuters sent questions to IARC’s Straif this month and the agency replied on his behalf. In response to whether its assessment of benzene had shortcomings, IARC said it did not. “In general, the exposure section of the IARC monographs does not contribute to the overall evaluation of the agent,” the agency said in an emailed response to Reuters. “Therefore, the section on exposure is not intended to exhaustively review the existing literature, but to describe human exposure situations that are pertinent to the evaluation.” (In other words, IARC’s classification of a substance depends on animal and human studies of its ability to cause cancer, not on how much people are exposed to it.)

What troubled Kopstein most, he said, was IARC’s reluctance to take action, even though the agency knew its statements on benzene exposure were being cited in litigation in the United States, and even though Kopstein was not the only scientist to have raised concerns about them. Another expert in the field had already published a commentary also saying the assessment was flawed because it was based on an incomplete review of the scientific evidence.

In a “note to reader” in its report covering benzene, IARC, which is based in Lyon, France, says that “every effort” is made to ensure its monographs are conducted as accurately as possible but that “mistakes may occur.” It asks any readers who find errors to communicate them to staff at its monograph section, “so that corrections can be reported in future volumes.”









Yet in an email on April 28, 2015, Straif told Kopstein there was no plan to amend the IARC monograph that evaluated benzene.

Dissatisfied, Kopstein decided to make his exchanges with the cancer agency public. He told Reuters: "IARC is foolishly burying its head in the sand, assuming this is going to go away. But I'm a very obstinate person. I'm going to see this through."

EXPOSED

Despite its global influence, IARC is a relatively small organization with a budget of 43 million euros ($53 million) a year. The agency is funded by around 24 IARC member states, and since 1985 has received more than $48 million from American taxpayers via grants from the U.S. National Institutes of Health. Some $22 million of the NIH funding has gone to IARC’s monograph program.

Since 1971, IARC has looked at more than 1,000 substances and has designated many as unclassifiable in terms of cancer-causing potential. It has classified around 500 as either carcinogenic, probably carcinogenic, or possibly carcinogenic to humans. Only one substance – an ingredient in nylon called caprolactam – has been classified by IARC as probably not causing cancer.

Some of the agency’s assessments – particularly recent ones on red and processed meats, coffee, the weedkiller glyphosate and mobile phones – have sparked global controversy and fuelled investigations into IARC by U.S. congressional committees. Last year’s Reuters reports on IARC’s glyphosate assessment also provoked strong reactions, from both activists opposed to genetically-modified crops and business-friendly Republicans in the United States. The passions reflect the influence of IARC’s monographs, and how interest groups across the political spectrum seek to exploit them to their own advantage.

“INCOMPLETE REVIEW”

The agency’s monograph reviews also regularly play a part in so-called “toxic tort” litigation cases in the United States – personal injury lawsuits in which plaintiffs claim that exposure to a chemical or substance caused them injury or disease.

One report cited in litigation is IARC’s Monograph 100F – the findings of a review conducted in 2009 of 33 chemicals, including benzene, and occupations related to them. The 100F benzene assessment had already attracted criticism from Peter Infante, one of the expert scientists on the IARC working group that had carried out the assessment.

Infante, who has studied benzene for 40 years, was formerly a director at the

U.S. Occupational Safety and Health Administration, which sets standards for workplace safety. He was dissatisfied with the way IARC’s assessment had been conducted and with its result. In 2011, he published a detailed critique in the American Journal of Industrial Medicine, which said the IARC benzene assessment was the result of an "incomplete review and discussion of the data,” and that some of its conclusions were “contradictory.”

He recommended that IARC hold a further monograph meeting dedicated to a full review of benzene on its own. Infante, who also frequently testifies as an expert witness for workers in benzene litigation, declined to comment for this story.

In response to Infante’s 2011 critique, Straif, the head of IARC’s monograph program, sent a joint letter with two other senior IARC staff to the journal. It said that the 2009 IARC meeting had suffered from restraints on time and resources, but that the discussions on benzene had been “the most extensive discussions at the meeting” and that IARC had “great confidence” in the ability of its expert panels “to reach sound evaluations.”

In answer to questions from Reuters this month, IARC said its 2011 letter had responded to Infante’s concerns. That letter, published as a commentary in the same journal as Infante’s critique, also said IARC was planning to schedule a benzene-only review to examine the chemical in more depth. Yet several years later, nothing had changed – as Kopstein discovered while working on litigation involving benzene.

In late 2014 and early 2015, he was an expert witness in two cases where people who had worked with benzene were claiming their exposure to it had caused them to become sick. In one case, plaintiffs were suing their employer for compensation, and in the other, they were suing product manufacturers. Kopstein was an expert witness for the plaintiffs. Experts for the defendants cited IARC’s 100F benzene review, conducted in 2009, whose full findings had been published in 2012.

IARC told Reuters it had no control over how its assessments are used in litigation.

In the 100F review, IARC had classified benzene in its highest rank of human carcinogens – Group 1 – mainly due to evidence that it can cause leukemia. But digging into its detail on potentially hazardous exposure, Kopstein found the IARC assessment relied heavily on a few studies which, he says, suggested the majority of occupational exposure levels were generally low. The studies did this, he says, because they limited their examination to products, such as honing oil used in grinding metal, which contained only small amounts of benzene and were not commonly used. So, while IARC was correctly gauging the danger of benzene itself, he concluded, the agency was giving unrealistically low estimates of how much of the carcinogen workers are exposed to in everyday jobs.

Like Infante before him, Kopstein struggled to understand why IARC had given little regard to wider scientific evidence on benzene exposure.

He also wondered why nothing appeared to have changed despite Infante’s concerns and IARC’s response to them. There had been no benzene-only review conducted; IARC’s 2009 assessment remained unaltered; IARC staff had not sought to alert readers of Monograph 100F to its potential limitations; and the monograph was being cited in litigation by companies seeking to show that workers suing them had not been unreasonably exposed to benzene.

Kopstein took the matter up with Straif, the head of IARC's monograph section, first writing to him on March 18, 2015. Getting no response, Kopstein followed up with a series of further emails – to Straif; to IARC’s director, Chris Wild; and to some of the agency’s U.S. funders.

He says he received little substantive response. “It was clear to me that they didn’t take me seriously,” Kopstein said.

IARC told Reuters it had “responded to all of the scientific issues Dr Kopstein raised.” Kopstein disputes that claim.

Kopstein also sought the attention of Martyn Smith, another experienced expert witness in U.S. litigation cases who has also served on IARC working groups. Smith promised to discuss Kopstein’s concerns with Straif and get back to him.

In an email to Kopstein on May 15, 2015, Smith said Monograph 100F had “tried to cover too much (too many chemicals)” and “was hurriedly put together.” The task on benzene alone was substantial: There were at least 20 years of new scientific literature to review since the last time IARC had assessed evidence on the chemical in 1987.

“So I’m not surprised it has left out key findings or focused on the wrong studies,” Smith wrote in his email to Kopstein. “The problem now is how to correct it given all the other things IARC is doing with very limited resources."

Smith did not respond to Reuters requests for comment.

Straif, too, eventually replied to Kopstein. In a June 2015 email he said the exposure section of the benzene monograph had been “condensed” to “contain cost,” and that the review of the scientific literature on exposure was not “exhaustive.” Straif assured Kopstein: “Your recent correspondence and suggested literature sources will certainly be considered if the carcinogenicity of benzene is re-evaluated in the future.”

Nothing happened in time for the two legal cases involving Kopstein and people claiming they had been harmed by benzene exposure. The cases were settled out of court with undisclosed agreements.

AT ODDS

An opportunity to address the limitations of Monograph 100F came in October last year when IARC fulfilled its 2011 promise to Infante by holding a benzene-only review. For a week, 27 scientists selected by Straif and other IARC staff met at the agency’s headquarters in Lyon.

Kopstein had written a critique of the Monograph 100F benzene review, which he had published in the peer-reviewed scientific journal New Solutions. Knowing the meeting was coming up, he sent the critique in an email on Sept. 16, 2017, to the scientists due to be on the IARC panel the following month. He wanted them to be able to read about his concerns and take them into account. On Sept. 18, he also sent the critique to Straif and IARC director Chris Wild.

Asked by Reuters whether the working group for this new benzene review – known as Monograph 120 – had considered Kopstein’s views, IARC indicated that it didn’t. It said Kopstein’s article was a commentary, not a study. “The Working Group of the Vol. 120 Monographs meeting considered all scientific articles eligible,” IARC said. “This includes original data published in scientific journals, but not commentaries and letters to the editor as these are viewpoints.” Kopstein said this was contrary to what Straif told him in the 2015 email which promised his correspondence and suggested literature sources would “certainly be considered.”

A summary of the October 2017 meeting’s conclusions, published online in the Lancet Oncology journal on Oct. 26, said benzene would remain classified by IARC as a Group 1 human carcinogen, mainly due to evidence that it causes leukemia. On exposure – the section criticised by Kopstein for lacking rigor and detail – the IARC summary had only brief, unreferenced statements. It said the working group experts had “noted” that benzene exposures in indoor and outdoor settings had generally declined.

According to Kopstein, the statements are “totally at odds” with the published evidence he has pointed out to IARC and cited in his correspondence with IARC staff. “It showed me that IARC was not interested in arriving at the facts and communicating the facts to governments around the world,” he told Reuters.

Infante, the benzene expert and former Occupational Safety and Health Administration director who criticised IARC’s 2009 benzene review, has continued to work with IARC and supports the agency’s monograph program.

He was asked to attend the October 2017 meeting as an “observer” and, IARC said, was allowed to speak at it but not to vote on the review’s conclusions. IARC forbids observers from recording events or talking publicly about what goes on at its meetings. IARC says this is intended to “provide an atmosphere conducive to free and frank discussion.”

In several emails to Infante, Reuters asked whether he was satisfied with the outcome of the 2017 benzene review, and in particular with the section on exposure, which says “benzene concentrations have declined over time” and that occupational exposures are less than 1 part per million. Infante declined to answer.

IARC told Reuters it and its working group members “stand fully behind the scientific integrity of the process and the evaluations” of the 2017 benzene review.

Benzene exposure By Kate Kelland Photo editing: Simon Newman Design: Catherine Tai Edited by Richard Woods