Role of toxicology in regulatory processes 1

Dr R. B. Cope 1

The Role of Toxicology in Regulatory Processes

Rhian Cope BVSc BSc(Hon 1) PhD CGLPCP DABT ERT

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Presentation Structure

• What do regulatory toxicologists do?

• The jungle in which regulatory toxicologists live.

• Types of regulatory processes (high level).

• A quick interactive case study.

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What Do Regulatory Toxicologists Do?

• Regulatory toxicologists have the primary role of science-based advice on public and environmental health and safety issues associated with the use of chemicals, drugs and pesticides, by identifying potential health hazards and risks posed by exposure to such substances;

• Science = the body of reliable knowledge;

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• Regulatory toxicologists provide science-based (fact-based) advice to:– Governments;– Companies;– Health professionals;– Politicians– The public

on potential hazards and risks associated with chemical exposure so that appropriate risk management strategies may be implemented to protect the health of workers and the public.

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What Do Regulatory Toxicologists Do?• Toxicology is a science and operates as a science i.e. – A systematic enterprise that builds and organizes

knowledge in the form of testable explanations and predictions (hypotheses);

– Operates using the principles of critical rationalism and falsifiability (Karl Popper);

– In many ways, the regulatory process is an application of scientific principles: toxicologists on either side of the regulatory equation operate in a manner that attempts to deductively falsify their respective data-derived positions

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What Do Regulatory Toxicologists Do?• What toxicology is not:

– PR;– Sales;– Advertising;– Lobbying;– Spin doctoring;– Absolute guarantors of regulatory approval;

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There is no such thing as “safe”

There are safety properties and probabilities.

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The Jungle in Which Regulatory Toxicologists Live

• Hazard = any source of potential damage, harm or adverse health effects;

• Risk = probability that humans (animals, environment) will be harmed or experience an adverse health effect i.e. the chance that a hazard will realized;

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• Adverse event = the actual realization of risk.

– Adverse events WILL happen no matter what we do: simple matter of probability;

– Effective controls/risk management will hopefully make adverse events infrequent;

– Toxicologists routinely deal with the aftermath of an adverse event (i.e. post-market surveillance/remediation etc);

– Forensics – i.e. toxicology for the purposes of the law;(not just criminal).

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• Controls/Risk Management = the steps taken to reduce the probability of an adverse event;

– Physical, chemical, human factors, patterns of use, process control;

– CAPA/TQS/”well ordered and controlled system”/GLP/GMP;

– ALARA principle;

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• Controls/Risk Management = the steps taken to reduce the probability of an adverse event;

– How much money are we willing to spend versus how much risk is acceptable?

– What are the probable consequences of the risk management decisions?

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• Acceptable risk = The notion that there is some level of risk that most (majority) will find acceptable;

– Complicated by the problem of risk perception: a better definition might be

“the notion that there is some level of perceived risk that most will find acceptable.”

– This is social and political. It is NOT a scientific decision!

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• Acceptable risk is a social and political decision. It is NOT a scientific

decision! For example:

– Notion that a risk of 10-8 was the default acceptable risk was dreamt up in the early 1960’s by scientists in the US NCI. The number had absolutely no scientific basis; rather it reflected what that particular subpopulation of scientists felt was acceptable for cancer risk assessments derived from animal data;

– 10-8 was given the official stamp of approval by the US FDA in 1973;

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• Acceptable risk is a social and political decision. It is NOT a scientific

decision!

For example:

– In 1977 US FDA changed it to 10-6 for reasons of cost and risk:benefit;

– US EPA has decided that risks of 10-4 to 10-6 are acceptable;

– On average, a RfD or ADI derived by traditional methods represents a risk of about 10-4

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The Jungle in Which Regulatory Toxicologists Live• Risk perception = the subjective judgment that humans make about

the characteristics and severity of a risk;

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Factor 1 = Dread;

Factor 2 = “Control”; capacity to perceive and avoid the hazard

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• Social amplification (of risk perception)/risk amplification:– Defines how communications of risk events pass from the sender

through intermediate stations to a receiver and in the process serve to amplify or attenuate perceptions of risk.

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• Risk Communication: an interactive process of exchange of information and opinion on risk among risk assessors, risk managers, and other interested parties;

– Risk communication is a critical and ongoing part of risk assessment. If the stakeholders do not understand or do not accept the process (methods) or the risk assessment, it will not be accepted and stands no chance of being implemented;

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• Risk Communication:

– Ideally all stakeholder groups should be involved from the start;

– The language/communications have to be understandable;• The mere perception of deception is extremely powerful;• Lack of understanding feeds the adverse perception of risk and

its social amplification;

– Understanding feedback is critical.

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• Expectations of the social contract:

– Trust;– Not to be harmed;– To have at least the illusion of control;– Environmental justice;– Benefit > Risk;– To be informed.

• Political considerations:– To be seen to be informed;– To be seen to be in control;– To get re-elected (industry lobby, public opinion);– Regulation should not be overly burdensome.

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• Product stewardship:

– Advocate for the substance/product based on realistic estimates of hazard and risk;

– Counter risk/hazard perception and provide informed communication regarding risks and hazards;

– Environmental, health, and safety protection centers around the product itself, and everyone involved in the lifespan of the product is called upon to take up responsibility to reduce its environmental, health, and safety impacts.

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• Product stewardship:

– Objectives are to extend the product lifecycle, to inform the downstream users of the actual risks, to reduce social amplification of misinformation, to aid compliance with relevant controls, and to limit misuse;

– The reward for good product stewardship is the protection of the brand name (both commercial and regulatory), improved product lifecycle duration, and hopefully higher profit (both commercial and social).

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Humans have an inexhaustible capacity to make mistakes, with fatal toxicological consequences

Almost all regulatory toxicology systems assume normal usage, or usage that is compatible with the instructions (compliance).

(which people rarely, if ever, actually read)

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Orellanine from Cortinarius sp. Resembles diquat (bipyridal). Futile redox cycling in renal tubular epithelia.

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Toxicological risk assessors have a key role in human factors engineering.

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Do you know what this is?

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The consequences of misuse.Regulatory toxicologists have little power to prevent misuse other

than risk/hazard communication (education).

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Types of Regulatory Processes (High Level)

• Substances Requiring Permission to Market (Pre-Market Approval)

– Fundamental regulatory mindset: “substance is guilty until proven innocent”

– Commercial regulatory situation:

No Regulatory Approval = No Market

= No Product = No Return on Investment

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• Substances Requiring Permission to Market (Pre-Market Approval)

– Expectations of the social contract

Benefit > Risk

Up to the registrant (commercial entity) to establish that the net benefit outweighs the risk

Acceptable Risk Perception (without this, there is no market)

– Objective is to define the safety properties (hazard & risk) over the entire lifecycle of the product and for the given normal pattern/type of use

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• Premarket approval systems:

– Applies to pharmaceuticals;

– Applies to most agrochemicals;

– Applies to industrial chemicals (e.g. REACh, China REACh etc) in particular jurisdictions and circumstances;• Current exceptions include the TSCA (TSCA reform is

pending);

– Applies to direct and indirect food additives;

– Applies to cosmetics/cosmetic components in some jurisdictions (e.g. Australia).

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• Premarket approval systems:

– Companies/applicants take on the legal burden of ensuring appropriate safety properties for the proposed uses;

– Companies (regulators) take on the legal burden of regularly reassessing the safety properties of substances;• New information;• New formulations;• New uses;• Legally mandated reassessment periods.

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• No premarket approval required– Fundamental regulatory mindset:

“substance is innocent until proven guilty”

– There is increasing public pressure on these types of regulatory systems;• EU REACh is a classical example of a shift from the

“innocent until proven guilty” to the “guilty until proven innocent” paradigms;

• Increasing pressure to regulate cosmetics, cosmosceuticals and nutriscueticals.

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• No premarket approval required

– Classically applied to cosmetics;

– Classically applied to tobacco (no longer true in the USA);

– Classically applied to industrial chemicals in the USA (TSCA);

– Classically applied to consumer care products (e.g. US CPSC )

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• No premarket approval required

– The burden of establishing acceptable safety properties for a substance lies with the regulators, not the companies;

– Legal liability lies with the companies, not the regulators;

– Politically, the regulators are usually blamed if something goes wrong!

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A Case Study.

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What would you do if you were: (a) the minister for mining? (b) a mine worker; (c) a government regulator; (c) the product steward in the company that made and marketed products from this commodity ; (d) owner of the house that the products were used in; and (e) a regulatory toxicologist/toxicological risk assessor?

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What would you do if you were: (a) a government regulator; (b) the mining company that owns and operates this mine?; (c) a regulatory toxicologist?

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Is this an acceptable use of this material?

What would you do if you were: (a) a government regulator; (b) a member of this community; and (d) a regulatory toxicologist?

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Is this an acceptable use of this material?

What would you do if you were: (a) a government regulator; (b) a member of this community; and (d) a regulatory toxicologist?

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What would you do if you were: (a) a government regulator; (b) the company that made and marketed products from this commodity ; (c) owner of this business; and (d) a regulatory toxicologist?

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Is this an acceptable risk? (major use of this commodity was for corrugated sheeting for roofs and fences; and for flat sheeting used in construction)

What would you do if you were: (a) a government regulator; (b) the company that made and marketed the sheeting for this use; (c) owner of the house; and (d) a regulatory toxicologist?

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Is this an acceptable risk?

Shoveling competition, Wittenoom mine, Western Australia, 1973.

Would you change your mind If you knew that 3 of the men in the photo subsequently died from mesothelioma, would this change your mind?

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If you knew that the material concerned is this?

Would you change your mind?

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A Systematic Failure of a Regulatory System

• 1st Century AD Roman historian Pliny noted that slaves wearing asbestos cloth sicken and die, and described the use of respirators made from animal bladders;

• 1898 British factory safety inspectors expressed concern about the 'evil effects' of asbestos dust;

• 1906 British Parliamentary Commission confirmed first cases of asbestos deaths in factories, and recommended better ventilation and other safety measures;

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• Despite knowing the risks, the company operated the mine from 1937 – 1966. Operating conditions in the mine and the associated milling operation were appalling throughout the entire course of its operation;

• Company was clearly warned of the hazards and risks of the operation in 1944;

• State government was warned in 1961 that: “the company was always aware that if it continued to run the mine without adequate dust suppression, they could be endangering the Wittenoom mine and mill workers to a very grave degree.”

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• First known diagnosis of mesothelioma in 1962;

• In 1962 the state Premier and Cabinet was warned about the situation at the mine. Nothing was done;

• State regulators and toxicological risk assessors had no legal power to shut down the mine;

• There was a very large surge in cases of mesothelioma in town residents and mine workers during the 1970’s and 1980’s;

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• The company was involved in a 30 year litigation battle regarding its actions at the mine. Company continues to deny any causal link between the mine/milling operations and disease;

• Eventually a settlement was reached with the former mine workers and the state government;

• By the time the settlement was reached, the majority of the workers affected by the mine/mill operations were dead.

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What Actually Happened: a Systematic Failure of a Regulatory System

• The the legal entity responsible for paying into the compensation fund was rapidly declared bankrupt (although the parent company responsible for the actions of the subsidiary had negligible losses and is still in operation);

• Very few of the affected workers or their families actually received compensation (either dead or could not overcome the legal barriers put in place regarding the compensation fund);

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• The state government initially tried to develop Wittenoom into a tourist destination!

• Finally, in 2006 the state government legally recognized the severe risks associated with the town and former mining/milling operations;

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Currently

• The town has been removed from all official maps;

• All unoccupied buildings in the town have been removed in line with the policy of “removal any easily visible sign of past habitation;”

• All utilities to the town have been disconnected;

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Currently

• All road signs indicating the location of the town have been removed;

• Town and mine operations declared a high priority hazardous site;

• Actual remediation has not been attempted due to high risk and cost;

• People still live in the town (refuse to leave).

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Life is a fatal process. Most of us will not die from chemical exposure.

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Role of toxicology in regulatory processes 1

Documents

risk dr

regulatory equation

regulatory toxicologistslive

level of risk

default acceptable risk

hazard dr

risk management decisions

communications of risk