1 January 2020

Pesticides and Endocrine Disruptors: How we Lost Track of Scientific Focus

Rainer von Mielecki

Vice President of Global
Public & Government Affairs
Crop Protection, BASF SE

Hormones were discovered about 100 years ago and scientists have been looking at their impact on living species ever since. More recently, such investigation has expanded to chemical substances that impact the endocrine system, such as birth control pills and even crop protection products. However, it has often been muddied by premature conclusions about cause and effect that subsequently result in misleading communication to the public.

Today, public discussion about endocrine disruptors – probably due to publication bias – has focused on several useful chemicals, ignored benefits versus real world risks, mixed political opinion with scientific assessment and subsequently, has led to regulations that are not in the best public interest. Unfortunately, all of these efforts set us back in endocrine science, rather than advance it.

Looking back on my 30-year career in endocrine science, it seems we’ve lost track of scientific focus along the way. This should be a wake-up call to all stakeholders to regroup on and rethink the “endocrine disruptor debate.” Applying the highest standards of science to regulation, after all, should not be debatable.

Discovery of Endocrine Activity

Endocrine science arguably began in 1905 when Ernest Starling, a professor of physiology at University College London, UK, first used the word “hormone.” Derived from a Greek word meaning “to arouse or excite,” hormones he defined as “the chemical messengers, which speeding from cell to cell along the blood stream, may coordinate the activities and growth of different parts of the body.” Then Friedrich Gudernatsch found in 1912 that extracts of horse thyroid tissue can induce precociously the complete metamorphosis of frog tadpoles into adults. And in 1939, Adolf Butenandt won the Nobel Prize for discovering the chemical structure of the female hormone estrogen.

As hormones are involved in many developmental processes, including sexual differentiation, libido, ageing and reproduction, they have caught public interest and imagination more than many other biological functions. In other words, dealing with hormones is highly emotional. I learned that at the beginning of my career in 1986 when I was responsible for correspondence between German pharmaceutical company Schering AG and transsexual people, who were helped by the company’s hormonal products with their sexual identity, and with concerned patients who were afraid of the contraceptive pill’s potential side effects, such as cardiovascular disease or breast cancer. (Schering developed the first oral contraceptive pill in Europe in 1961.)

Public discussion about endocrine disruptors has focused on several useful chemicals, ignored benefits versus real world risks, mixed political opinion with scientific assessment and subsequently, has led to regulations that are not in the best public interest.

Wanted and Unwanted Effects

At Schering in those days, a large number of scientists – from pharmacologists, endocrinologists, toxicologists to gynecologists and epidemiologists – were working on assessing potential relationships between exposure to hormones and disease in order to determine so-called unwanted effects. The results of their thorough research found its way into drug package inserts for patients and consumers. People that used Schering drugs or those of other pharmaceutical companies often found technical drug information difficult to understand. Scientists, whether from academia, industry or government institutions, found it difficult to talk to non-scientists in a meaningful way. The reason is because science is complex and most scientists do not want to oversimplify so they tend to confuse non-experts with a lot of detail, open questions and scientific uncertainties.

And this is where the problem regarding endocrine disruption started. How can anyone who is not an expert (we are all non-experts in most areas) know whether a chemical substance causes health problems, say endocrine disruption, or not? What do we know for certain? Is there a high or low probability of potential damage – or none at all? Who should we believe?

One issue when discussing potential unwanted health effects is to convince non-experts that two incidents occurring at a similar time are often not causally linked. For example, as ice cream sales increase, the rate of drowning deaths increases sharply. Therefore, ice cream consumption causes drowning.

The aforementioned example fails to recognize the importance of time and temperature in relationship to ice cream sales. Ice cream is sold during hot summer months at a much greater rate than during colder times and it is during these hot months that people are more likely to engage in activities involving water, such as swimming. The increased drowning deaths are simply caused by more exposure to water-based activities, not ice cream. The stated conclusion is false.

Psychologically, humans have a strong tendency to link similar, temporal events to the same cause even when they are not related. From a scientific point of view, such cause and effect links are often wrong. Experts and journalists should have communicated this general fact more clearly in the past.

At the same time, judgments need to be made and communicated once there is relevant evidence that two events are causally linked, then regulatory steps need to be taken to protect human health and the environment. For example, the Swiss pharmaceutical company Roche studied in the 1960s the product Accutane to treat severe acne. When animal experiments with rabbits showed a causal link to birth defects, the company immediately warned doctors and patients, and restricted use of the drug that was regarded as an essential treatment by dermatologists and psychologists. In 2001, the U.S. Food and Drug Administration announced a new regulatory scheme called SMART (System to Manage Accutane-Related Teratogenicity) requiring Roche to provide training materials to doctors, who have to sign and return a letter acknowledging they have reviewed the materials. With signed letters in hand, Roche sends stickers to doctors, who must place them on prescriptions given to patients after confirming a negative pregnancy test. In addition, prescriptions can only be written for 30 days and not refilled, thus requiring a new pregnancy test for each prescription. In this case, communication was rapid and effective.

It often takes a thorough expert assessment to determine whether a cause and effect relation is plausible or not. As the cases above show, there is no reason to ban ice cream sales during summer, however, pregnant women must be prevented from taking Accutane.

Psychologically, humans have a strong tendency to link similar, temporal events to the same cause even when they are not related. From a scientific point of view, such cause and effect links are often wrong.

Information and Informed Decision-Making

Back to my days at Schering: Did it matter to regulators whether the potential unwanted effects of the birth control pill were causally linked to taking a drug or not? Only to some extent. Regulators insisted that hints of potential side effects were included in the package insert and patient information regardless of whether a causal link had been established. The drug itself was not banned as this was not seen as a proportionate action to the potential risk.

Thirty years later, research on hormones in the medical area goes on and by the very nature of research, there are always new things to be discovered and many questions remain yet unanswered. The “pill scares” of the 1980s have ebbed and the media seem to have lost interest. Oral contraceptives, which we would probably call endocrine disruptors today, are a frequent choice for family planning and users weigh the benefits higher than risks. Common understanding in the assessment of benefits and risks among the public, regulators and scientists has increased over time.

Rise of Endocrine Disruptors

In 1992, I left Schering and joined the Swiss chemical company Ciba. By 1995, I was asked to join a team tasked with enhancing the company’s understanding of so-called “endocrine disruptors.” Ciba was interested in this area as it produced anti-fouling chemicals for paints to control algae growth on the underside of boats. These chemicals were suspected as potential endocrine disruptors and later banned internationally because of endocrine-disrupting effects on marine invertebrates (e.g., snails). Joining Ciba from a pharmaceutical company whose core competency had been endocrinology, I was not immediately convinced that extremely low-dose environmental residues from chemicals could lead to massive and broad unwanted effects. Clearly, more research was needed to better define the issue.

In the early 1980s at university, I learned about the endocrine-disrupting effects of DDT on eggshell glands of birds of prey. The birds had obviously consumed meat from dead sheep that were previously bathed or dipped in a high-dose DDT bath to kill insect parasites on their skin. Exposure to and dosage of potent DDT must have been so high that damage was caused to the birds. Further research established that those findings were dose-dependent. It is regrettable that this happened. But could “endocrine disruption” be caused by extremely low doses and unclear exposure?

It had taken more than 20 years to go from Schering’s first structural identification of estrogen and Butenandt’s discovery to marketing the first European contraception pill Anovlar. Natural estrogen does not pass through the human liver without being metabolized. Schering and others had to synthesize a highly persistent estrogen called Norethisterone in order to reach target organs in the body after passing through the liver. This synthetic estrogen had to be very potent in order to interfere reliably with the female menstrual cycle. On the backdrop of that knowledge, and even when taking into account that the route of exposure may not always be oral, I find it difficult to believe in the real world relevance of low-dose “endocrine disruptors” in the environment.

Environmentalists Leading Debate

With even greater surprise I realized in 2008 while working for Germany’s BASF SE Crop Protection that the new European Pesticide Regulation 1107/2009 was to include hazard-based cut-offs for endocrine disruption. What happened?

A considerable number of environmentally concerned scientists in the U.S. and Europe, many from academia and often in close collaboration with environmental NGOs, had undertaken research for more than 30 years on potential endocrine hazards based on the conviction that the release of some synthetic chemicals in the environment posed a major risk and had to be significantly reduced or even banned. Reports from these scientists on the potential adverse effects of chemical substances such as phthalates, Bisphenol A or flame retardants in small quantities ubiquitous in modern consumer products and packaging, led to media reports and consequently, public and regulatory concern.

Scientific Shortcomings

Publications on “endocrine disruptors” were neither able to address uncertainties nor shed light on the true extent of the problem. Also, probable causal relationships based on relevant scientific signals or evidence have not been established in many cases. Many findings could not be confirmed in repeated experimentation. Such failure to reproduce results may infer that there are other variables or factors inadequately controlled which influence the outcome of these studies. In other words, biology is more complex than scientists understand.

On this backdrop, concerned environmental and other scientists started to focus on concepts such as endocrine disruptor “low-dose effects,” “non-monotonic dose responses” and “cumulative toxicity” that most probably should not have relevance to current regulatory practices. Not surprisingly, a key scientific paper published in the prestigious journal Science, which helped launch the movement against endocrine disruptors, was retracted and its author found to have committed scientific misconduct. Another debate that caused public concern had been about endocrine disruptors and observations of falling sperm counts in men in Denmark. These first findings could not be repeated in a publicly paid for follow-up study and its contradicting results were never fully published in a peer-reviewed journal. The data from 16 years of comprehensive sampling of the most relevant men showed that there was little evidence of any decline in sperm counts from the thousands of samples taken.

Risk of Only Seeing What You Want

Where does this story leave me when considering endocrine disruptors, scientists, regulators and the public? There is a real risk that scientists with a political agenda – and certainly, we all have our agendas – may fall victim to bias, such as “concerned environmentalists” seeing what they want to see.

Those scientists tend to disregard the falsifiability paradigm of Sir Karl Popper that was hammered into my brain by my biology professor when I studied at the Free University of Berlin 40 years ago. For Popper, a theory in the empirical sciences can never be proven, but it can be falsified, meaning that it can and should be scrutinized by decisive experiments. If the outcome of an experiment contradicts the theory, one should refrain from ad hoc maneuvers that evade the contradiction merely by making it less falsifiable.

It is my understanding that many environmental scientists as well as other scientists in the endocrine field, try hard to support their hypotheses and not expose them to falsifiability. They should ask to be challenged by the more traditional hormone scientists in pharmacology and toxicology. Unchallenged hypotheses do not lead to new insights, rather they carry the risk of bias and controversy in the scientific community. Political opinions may then trump science and regulators make decisions that may not be in the best public interest. Most importantly, society will waste resources that could be better focused on further advancing science.

There is a real risk that scientists with a political agenda may fall victim to bias, such as “concerned environmentalists” seeing what they want to see.

Potency Matters

Moreover, consumers could be manipulated to their disadvantage. If not shared with them (other than in drug package leaflets) whether high or low chances of a causal relationship between exposure to a chemical and a disease exists, they will not be able to make rational decisions. If they are made to believe their health is at risk from endocrine low-dose effects or cumulative effects of certain chemicals in the environment, they will find it hard at the same time to identify risks from potent chemicals or those with high-dose effects and learn to avoid them. Potent chemicals could include pharmaceuticals (e.g., hormonal medications, certain pain killers or antipsychotics), whereas less potent food ingredients may be consumed above a healthy physiological level (e.g., sugar at high doses).

Pharmaceuticals and certain food ingredients have to be potent and/or highly dosed in order to produce desirable effects. However, chemical residues in the environment normally do not have such effects, nor are they intended to. The hormonal system has developed robust stability throughout human evolution in order to protect individuals and species against environmental fluctuations to low-potency compounds. Only very strong environmental interferences, such as birth control pills, can break this robustness, not low-dose residues of natural or synthetic chemicals in the environment.

Food for Thought

Working for a chemical company, it is not up to me to tell others how to do better, nor am I the most qualified individual to do so. However, based on my 30-year, limited experience with hormonal science and endocrine disruptors, here are a few discussion points:

  1. Scientists from academic and industry backgrounds alike should be more open and honest and go back to Popper’s falsifiability paradigm. Experts from all areas of expertise – from toxicology, pharmacology and endocrinology to epidemiology should critically look at today’s hypotheses in endocrine disruptors and together define a way forward. The values and beliefs of one expertise group – concerned environmental scientists – should not trump all others. It is incumbent on regulatory scientists to conduct a weight of evidence analysis of hypotheses proposed by endocrinologists and NGOs, whereas it is incumbent upon endocrinologists and NGOs to understand how regulatory science is performed (e.g., the impact of general toxicity on endocrine endpoints, potency, exposure, etc.). If there are any deficiencies in chemical/toxicity management, these scientists should work together to address shortcomings. Neither scare tactics nor deniability will improve the safety of new chemicals in the future.
  2. Regulators should base their decisions on real world observations in order to protect the health of people and the environment most effectively. To concentrate regulation on speculation rather than on probable causes takes the focus away from what really matters and thus may do more harm than good. Decisions should be based on science, not speculation.
  3. Consumers should receive information that differentiates between the most probable unwanted effects and the most unlikely effects, such as drug patient leaflets. Experts owe this to non-experts, particularly in an area that is so heavily influenced by emotions as hormones. This will enhance informed decision-making and may lead to rational consumer behavior and better political debates.

Finally, I am worried if the endocrine disruptor debate continues as it is today, we will keep “looking under the wrong lamp post” instead of identifying relevant causes of endocrine-related diseases. This will not provide additional protection for the environment, science, regulation or consumers. The fathers of hormonal science – Butenandt, Starling and Gudernatsch – would like us, I am sure, to build on their formidable heritage from 100 years ago to ensure that cause and effect are linked by evidence based on the highest standards of today’s science.

Rainer von Mielecki is vice president of Global Public & Government Affairs Crop Protection at BASF SE in Ludwigshafen, Germany.

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