presentation at efsa, parma, by m. kogevinas (isglobal, isee) on pesticides risk assessment

Presentation at workshop by EFSA (European Food Safety Agency) at Parma, Italy

on November 21, 2017 on pesticides risk assessment

Critical review of the EFSA approach

Manolis Kogevinas MD, PhD President,

International Society for Environmental Epidemiology (ISEE)

Barcelona Institute for Global Health (ISGlobal)[email protected]

@KogevinasM

EFSA 2017, Parma

mailto:[email protected]

Notes on previous slide

• Excellent workshop organized by the PesticidesCommittee of EFSA on how to incorporateepidemiology in the risk assessment they are doing for the European Commission. EFSA corresponds to the US FDA but focuses only onfood. The pesticides committee exceptionally alsodeals with occupational exposures to pesticides. The usual difficulties in cross-discipline discussions occurred but overall the workshop was excellent and helped communication.

Man’s mind cannot grasp the causes of events in their completeness, but the desire to find those causes is implanted in man’s soul. And without considering the multiplicity and complexity of the conditions any one of which taken separately may seem to be the cause, he snatches at the first approximation to a cause that seems to him intelligible and says: “This is the cause!”

Leo Tolstoy War and Peace; Book Thirteen: 1812; Chapter 1


• My summer readings. Leo Tolstoy refers to theNapoleonic wars and how do persons and societies take decisions. Isn’t this a perfect fitfor our science?

We have a problem with health risk assessment of pesticides (not only pesticides; not only epidemiology)

The most complex issue in epidemiological studies of pesticides is exposure assessment. There are solutions to this

“Exposome” approaches open new possibilities for research and advanced risk assessment bridging toxicology and epidemiology

We need more funding on pesticides research The EFSA Scientific Opinion could be significantly improved EFSA needs to standardize protocols

Main messages


The complex issues of risk assessment of pesticidesare also found in many other exposures, e.g. endocrine disruption, water contaminants. Also themany problems with RA of pesticides are notspecific to epidemiology but to all other disciplines. What distinguishes pesticides from other exposuresis that the about 500 of them used in the EU are regulated (however this regulation applies in practice). By contrast regulation does not exist formany other components of mixtures or complexexposure circumstances

Pesticides and cancer

Lindane, classified as human carcinogen (Group 1) in relation to risk of non-Hodgkin Lymphoma (IARC 2015; D Loomis, LancetOncol, 2015)

Why is there only one insecticide classified as human carcinogenby IARC/WHO?

Lack of convincing evidence for other pesticides clearly shows thedifficulties in evaluating the carcinogenicity of many chemicalagents in human populations


I chaired the IARC Monograph that classified the one and only pesticide in Group 1 (definitive carcinogens), Lindane. One of the reasons for not having many more pesticides classified in Group1 is that not necessarily many of the pesticides we use are actually carcinogens, though they may show acute toxicities. However, this cannot simply be the only explanation and certainly the most important reason for having only one pesticide in Group1 refers to difficulties in research. Many of the most toxic chemicals we know show multiple toxicities, for example affect neurodevelopment, growth, cardiometabolic, and are also genotoxic. Pesticides that have been shown to have multiple toxicities could also be expected to be genotoxic but we still cannot prove this. This is because of the difficulties in research (not only epidemiologic research). In the same monograph that we evaluated Lindanewe also evaluated DDT. It is really unlikely that DDT is not carcinogenic to humans (at high and prolonged doses) but still applying IARC rules, we could not classify DDT in group 1.

Pesticides and cancer

Lindane, classified as human carcinogen (Group 1) in relation to risk of non-Hodgkin Lymphoma (IARC 2015; D Loomis, LancetOncol, 2015)

Why is there only one insecticide classified as human carcinogenby IARC/WHO?

Lack of convincing evidence for other pesticides clearly shows thedifficulties in evaluating the carcinogenicity of many chemicalagents in human populations

• standard environmental toxicity tests used to license pesticides are performed on particular test species and have limited predictive power when chemicals are used widely (see also Milnerand Boyd, Science 2017)

• low level of trust in current toxicology testing regimes because of serious difficulties to encompass the full range of toxic effects that could emerge when a pesticides is used at scale


Situations of other disciplines that have failed to do good predictions on pesticides, e.g. environmental tox (quotes are from Milner and Boyd’s commentary in Science, that is excellent). Important to note that exposure and effects may differ significantly between short term tox tests and long term application in the field


The most complex issue in epidemiological studies of pesticides is exposure assessment. There are solutions to this (see presentation by Laura Beane Freeman)



Main messages


Exposure misclassification is extremely important in pesticides research; I cover this very briefly because other presenters discussed this issue at length

• Seasonal

• Often outdoors but also indoors

• Highly variable

• Type of agent and exposure

• Biological, chemical and physical

• Individual agents (active ingredients; adjuvants)

• Intensity, duration and frequency

• Multiple agents

• Multiple routes

• Not limited to farmers

(slide modified from Hans Kromhout, Univ Utrecht)

Nature of exposures in agriculture





Main messages


The term Exposome used to indicate in reality modern environmental epidemiology using new approaches both for exposure assessment and for evaluation of mechanisms

The Exposome

Recognizing the disparity in current knowledge between genes and environmental exposures, Chris Wild (2005)

defined the “exposome” representing all environmental exposures (including those from diet, lifestyle, and

endogenous sources) from conception onwards, as a quantity of critical interest to disease etiology.

E


Big G means a lot of money and attention forgenetics. Little E means little money and attention to the evaluation of Environmental exposures

“Modern” Epidemiology

(Slide from Perry Hystad, Oregon State University)


John Snow, Broad street pump. I make reference to the fact that for a long period Environmental Epi continued working with this principle, ie a source, and exposure evaluated in concentric cycles around the source. Works some times and for some exposures, but too simplistic for most of what affects human populations


(Slide from Perry Hystad, Oregon State University)


Refer to the new tools that have revolutionized environmental exposure assessment. Not all of them are relevant for occupational pesticides epidemiology


• Refer to the capacity to evaluate “internal” exposomeand mechanisms. The right panel is from our study on metabolomics of swimming in a chlorinated pool (see Karin van Veldhoven, in press) in Barcelona, distinguishing clearly metabolic patterns before and after a 40 minutes swim and identifying new pathways (well you cannot see the pathways in this graph). The left hand panel is from Casals-Casas and Desvergne, 2011, on pathway perturbation on endocrine disruption. A very similar approach to what toxicologists do with AOPs (adverse outcome pathways)





Main messages

Most of the evidence in human from studies examining mainly other risk factors (hence no detailed analysis of pesticides-hence not surprising that these data cannot be used in risk assessment)

Some major studies funded (a mistake to consider only AgHealth)

We need 100M€ (indicative amount) to do a couple of new powerful cohort studies in different settings. Multidisciplinary, extensive industrial hygiene, repeated biomarkers, omics, long term follow-up

Serious underfunding of research on pesticides


Self evident. Unless we get more funding to do pesticides research we will come back in 10-15 years at EFSA complaining about problems of research. If 100 million Euros seem a lot to you, look at the R&D budgets of big food-chain companies





Main messages

The EFSA Scientific Opinion: a report on epidemiology

written by non-epidemiologists. An interesting

endeavour (for the authors) but not an EFSA document


EFSA did a serious attempt to incorporate epidemiology in the discussion of pesticides risk assessment. This is positive. The document however circulated is naive concerning epidemiology and it is surprising that the working group producing this document is basically non-epidemiologists (with few exceptions of a couple excellent epidemiologists participating as external advisors). It is problematic when this type of documents with a very unbalanced critique not clear understanding of epidemiological methos, become official EFSA documents

The EFSA Scientific Opinion: comments submitted by ISEE

• Epistemological (toxicologic studies versus epidemiology) • Mechanistic (favor ranking etc., rather than a integrated

assessment of knowledge)• Missing considerations (no advocacy for the necessary

substantial ongoing stream of funding for surveillance and post-marketing surveillance of pesticides that could strengthen our capacity to identify real life events, nor for expanded, diversified, well-funded, and more detailed epidemiologic studies being now concentrated in just some centers and labs)

• Vulnerability of study populations (strengths of epidemiology to examine real life conditions of exposure and disease, vulnerable populations, and real life outcomes that can happen and are seldom observed in vivo)


A summary of some of the comments sent by the ISEE Policy committee to the draft document circualted by EFSA (full draft can be found in EFSA’s web)

The EFSA Scientific Opinion: comments by ISEE

• Writing: unequal; many parts valuable; overall could be improved

• Overall message of the report: epidemiology is not reliable, text making systematically broad generalizations

• Many cliché on causal inference, ranking of evidence etc• Important areas poorly covered, e.g. retrospective

exposure assessment and biomonitoring, post market surveillance

• Scope: unclear (or at least poorly described)


Specific comments on draft. Scope refers to the fact that a framework for risk assessment is produced by a specific panel while EFSA should have provided centrally these guidelines, similar for example to what IARC does. It is actually surprising that EFSA does not provide these guidelines centrally

Occupational Human carcinogens(Group 1- IARC)

• 118 agents in Group 1

• 57 are occupational or also occur in the occupationalenvironment (e.g. aflatoxins, SHS, radiations etc)

• Of those, 36 were identified as Group 1 before the year2000, and 21 after the year 2000


Making a point that most occupational carcinogens we have identified in Group1 (IARC) were identified through epi studies before the wider use of mechanistic data in hazard identification. This to contrast the repeated statements by toxicologists and basic scientists that epidemiology does not provide firm conclusions. Just amazing how these statements are repeated and become dogmas. Statements like “epidemiology has intrinsic weaknesses and does not allow conclusions but still concern” (this was mentioned by a key toxicologists at the EFSA meeting) are repeated in one or other way. This simply shows a very poor understanding on causal inference.

Probable Occupational Human carcinogens (Group 2A- IARC)

• 81 agents in Group 2A (probable carcinogens)

• 48 are occupational

• Of those, 20 were identified as Group 2A before theyear 2000, and 28 after the year 2000

• Use of evidence on mechanisms very important forthis group (upgrade from 2B-possible to 2A-probable)


Interesting statistics on 2A (probable IARC) carcinogens. Here we have more agents identified in recent years (by contrast to Group1), and most are through the combination of human, animal and mechanistic data. This is actually a very positive development of the last 20 years in IARC, i.e. that the evaluations take more formally into account all available evidence and mechanistic data are key part of the evidence

There is no predefined hierarchy in study design.

RCTs are good for clinical settings and not good for environmental,

occupational and many other exposures


Graph from NYT. One more repeated statement by tox, clinicians that RCTs (randomized controlled trials) are the gold standard. It is repeated so many times that this also has become a dogma. RCTs should not be taken as a gold standard because they are not applicable in most circumstances outside clinical settings and because they simply cannot respond to complex questions in population studies. Just asked the audience if they thought we should be doing RCTs on availability of guns and mass shootings. OK, an extreme example but that is why we have examples to make a point!

The EFSA Scientific Opinion: out of scope

Conclusions of the report (p58):‘The PPR Panel will specifically’:1) Collect and review all sources of gaps and limitations … , of the available epidemiological studies. 2) Based on the gaps and limitations identified in point 1, propose potential refinements for future epidemiological studies to increase the quality, relevance and reliability … This may include study design, exposure assessment…3) Identify areas in which information and/or criteria are insufficient or lacking and propose recommendations for how to conduct pesticide epidemiological studies in order to improve and optimise the application in risk assessment. … 4) Discuss how to make appropriate use of epidemiological findings in risk assessment of pesticides during the peer review process of draft assessment reports, e.g. WoE as well as integrating the epidemiological information with data from experimental toxicology, AOPs, mechanism of actions, etc.


Point made to EFSA to show that the report they produced were out of scope. The PPR (pesticides) panel does not have a single epidemiologist and they still see their job as making proposals on how we should be doing epidemiological studies. Getting feedback from other disciplines is very positive and desirable. Having however people who do not understand and are trained in epi methods defining the protocols we should use in our studies is another business. Interesting discussion at questions times, after my presentation where the Chair of the panel said that 6 out of 8 panel members were actually epidemiologists because they had co-authored sometime in their life epidemiological papers. Oh well, this is how cell biologists understand epidemiology…





Main messages

We suggest a balanced panel, addressing the overall production of pesticide science, aiming to enhance the integration and advancement of knowledge.

We urge EFSA to develop and apply standardized protocols for risk assessment rather than ask each panel to improvise and produce position papers on issues that are not within their area of knowledge as is the case with the pesticides paper.

ISEE’s comments to draft


Comments by ISEE Policy committee to EFSA. Contrary to other EU or International organizations, EFSA has not developed as much formal protocols and depends very much on ideas and approaches developed by each Panel (mostly small panels, specialized on specific topics that are not always sufficiently multidisciplinary).

We urge EFSA to consider in developing these protocols relevant guidelines for systematic review of evidence that already exist e.g. in WHO.

We urge EFSA to consider that older reports such as the WHO “guidelines for guidelines” have been modified to enable the application of a wider more holistic perspective concerning the types of evidence to be used

ISEE’s comments to draft

Notes on previous and subsequentslides

• Comments by ISEE Policy committee to EFSA.

Science is one and epidemiology works integrated with other sciences;

Epidemiology as any other science is advancing, and to further contribute to the assessment of the health effects of pesticides requires of independent and rigorous research well-funded, as well as the input from post marketing surveillance;

We have to take advantage of our understanding of the “exposome” and need to consider it on the real vulnerabilities of population, only provided through population (epidemiologic) research.

The role of epidemiology

• Transformational change in the breadth and depth of exposure assessment that would improve integration with and responsiveness to toxicology and epidemiology• Questions as to whether or how the data now being generated can be used to improve risk-based decision-making• We need to invest in common understanding and exchange of ideas and link modern exposure assessment, molecular epidemiology/exposome with toxicological approaches on mode of Action/Adverse Outcome Pathways. Both are in combination essential to establish evidence based risk assessments and policies

New approaches for risk assessment

thank you, on behalf of theInternational Society for Environmental

Epidemiology (ISEE) and EPICOHAcknowledgments

ISEE Council: Beate Ritz, President elect; Greg Wellenius and Chang-Chuan Chan, Councilors;

ISEE Policy Committee: Michal Krzyzanowski, Chair, Carlos Santos Burgoa, Tony Fletcher, Silvia Medina, Erik Lebret

EPICOH: Roel Vermeulen, Chair; Aaron Blair, Hans Kromhout

presentation at efsa, parma, by m. kogevinas (isglobal, isee) on pesticides risk assessment

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