LONDON (Reuters) – 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.
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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
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
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
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.
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
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.”
Despite its global influence, IARC is a relatively small organization
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
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.
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
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.
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.
