Sep 25, 2019

Ep 194: Edward Calabrese - Toxicologist, University of Massachusetts - Amherst

University of Massachusetts - Amherst
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Show notes

From insects to public health (1:37)
1:37-9:04 (Ed explains how the field of toxicology arose from the environmental movement of the 1960s. He discusses his journey from entomology to public health and his position now at the University of Massachusetts - Amherst.)

Q. How did you come into the field of toxicology?
A. When Ed Calabrese was an undergraduate student, he noticed the widespread concern of pesticides that sprung out of the awakening of the environmental movement in the 1960s and with the publication of Rachel Carson’s Silent Spring. Ed was hired by an advisor to collect intertidal samples to analyze pesticide residue. This work inspired Ed to become an insecticide toxicologist, which he pursued in a PhD program in the 1970s. During the program, however, Ed was driven towards public health applications rather than entomology. Ed’s first faculty position was at the University of Illinois’ School of Public Health in the environmental and occupational medicine department. Here, Ed looked into issues such as radium-226 in drinking water in some Illinois communities.

Ed grew up near Cape Cod and prefers the country life to living in Chicago. The University of Massachusetts - Amherst fit Ed’s favored lifestyle and so he joined their School of Public Health. Ed has been a toxicologist faculty member there for 43 years and still enjoys his work today.

Similarities between DDT and radiation exposure (9:05)
9:05-18:46 (Ed explains the similarities in studying chemical toxicology and radiation biology. He also discusses the challenges of human-based studies.)

Q. Can radiation be studied in the same way as DDT?
A. The fields of chemical toxicology and radiation biology did not mature together and had little inter-field communication. Ed saw this as a problem because it prevented scientists from seeing comminalities. Ed studies the adaptive responses to low-level exposures and notes the similarities between the two fields is striking. For instance, Ed sees the same biological responses to low-level DDT exposure as radiation exposure.

Measuring the toxicological effects of contaminants depends on the agents that are studied and the biological material that is evaluated. Over the past 30 years, the studies have shifted away from using mice and rats to using cell cultures. This is because cell culture and invitro studies allow for more concentrations to be tested and enable more replicability of studies. Studying low-dose effects is even more difficult in human studies, also known as epidemiology studies. Human populations are highly variable, meaning the magnitude of adaptive responses to low-dose effects is modest and the underlying mechanisms are harder to detect. This makes it difficult to detect adverse or beneficial changes and can cause differing results between studies.

The LNT model versus hormesis (18:47)
18:47-26:16 (Ed explains what caused the interest in studying the effects of low-dose exposure and the differences between the LNT model and hormesis.)

Q. What motivated us to look into the epidemiological effects of low-dose contamination?
A. Environmental legislation, such as the Clean Water Act, began surfacing in the 1970s. This was also the first time that the US focused on chemical carcinogens and the need for a policy to assess contamination risk. The National Academy of Sciences had previously recommended that ionizing radiation be evaluated for a linear dose response relationship. In the mid-1970s, the Environmental Protection Agency (EPA) applied this guidance to chemical carcinogens as chemical carcinogens and ionizing radiation act via the same mutagenic mechanism. By 1979, the EPA used the linear dose response relationship model to establish the first carcinogen-based drinking water standard, which was then applied to many other chemicals. Linear dose response models, known as linear no-threshold (LNT) models, established acceptable low-level exposure risks. This required industry to adopt costly new plants, strategies and technology.

At the same time, the EPA began seeking out the responsible parties to clean dumpsites around the country. Carcinogen cleanup costs were driven by the LNT model. This sparked conflict between industries and the EPA because the national toxicology testing program had to extrapolate data and the EPA always chose to favor on the side of safety. The LNT model also meant that the EPA would not declare a threshold. This caused people to become interested in hormesis, the biological response to low-dose exposures. Because of the J-shaped curve of hormesis, the risks of exposure were more easily distinguished from the LNT model.

In hormesis, dose is measured on the X-axis and response is measured on the Y-axis. Disease incidents, such as cancer or heart attacks, depict a J-shape dose response. Memory-enhancement drugs, for example, show an inverted U-shape dose response, which explain how performance is enhanced with exposure. The magnitude of the response is the same whether the subject is a plant, animal, cell or human.

Improving adaptive responses with low-dose exposure (29:19)
29:19-42:57 (Ed explains how low-dose exposures can improve adaptive responses.)

Q. Does this mean that low-levels of radiation are good for us or does it mean they are insignificant?
A. Organisms have the capability to adapt and will respond when cells are stressed or damaged. If exposed today to a low-level dose, the body’s adaptive response will last for typically 2 weeks. If the organism is exposed to a high dose during this period, they will have a greater ability to prevent harm from the higher dose. Humans tend to overcompensate in our adaptive responses. This not only allows us to repair damages, but also upregulates adaptive mechanisms, leading to overall improved performance. Moderate amounts of stress from low-level doses therefore induce positive hormetic dose responses. This has been seen with mercury, lead and ricin but also in a preconditioning study in rodents. The research showed that when preconditioned using a blood pressure cuff, shock damage in the rodents was reduced by 80%.

Low-dose radiation is good for health (42:58)
42:58-54:02 (Ed explains the difficulty of including hormetic dose responses in regulatory decisions. He also discusses a research project that shows the benefits of low-dose radiation exposure.)

Q. How do we get agencies to put regulations in a biological context?
A. Ed says this is the big question. Ed testified in the Senate on an EPA proposal to consider non-linear dose responses in risk assessments, including hormetic dose responses. Ed believes the data that has accumulated over the past decade points to this being necessary. There are many opponents to this because most believe that lower exposure is always better. However, we need some exposure to stress because organism health diminishes when stress is fully eliminated.

Ed attended a conference where a researcher presented a study that exposed mice to a radiation level of about 60 times higher than background doses. After 92 weeks, the exposed mice looked much healthier than the control group. Additionally, the exposed mice lived about 20 to 30% longer than the control group. Ed believes regulatory agencies must optimize health rather than separating law from public health. This position challenges the last 30 years of thought, but Ed believes challenging the regulatory agencies is just as the science proves that low-doses are good for health.

Retraining minds through exposure to Ed’s message (54:03)
54:03-1:01:13 (Ed explains that retraining the public and scientific community is needed to erase fear of low-dose radiation.)

Q. How can the idea of hormesis be pushed forwards to erase the fear of low-dose radiation?
A. Ed believes that both the public and scientific community have been brainwashed. Retraining people is the major challenge facing the industry. Ed sees hope because people ultimately want to live a healthy long life. Because many medicines are based on hormesis, self-interest will motivate people to save their hearts, hair and neurons without waiting for regulation to catch-up. Intelligent low-doses of stress enhance biological systems and Ed believes he can transform opinions by gaining more exposure to this hopeful message.

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