Regulatory toxicologists provide science-based advice to governments, companies, health professionals, politicians, and the public on potential hazards and risks associated with chemical exposure. Their role is to identify health hazards and risks posed by substances to allow for appropriate risk management strategies to protect public health. However, regulatory toxicology does not operate as public relations, sales, advertising, lobbying, or spin doctoring. Rather, it is a scientific discipline that builds knowledge through testable hypotheses. Regulatory toxicologists must navigate complex social and political factors like risk perception, communication, and what constitutes an "acceptable risk." Their aim is to advocate for informed and balanced decision making regarding chemical risks.

1. The Role of Toxicology in
Regulatory Processes
Rhian Cope BVSc BSc(Hon 1) PhD CGLPCP DABT ERT
Dr R. B. Cope 1

2. 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.
Dr R. B. Cope 2

3. 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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4. What Do Regulatory Toxicologists Do?
• 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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5. 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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6. What Do Regulatory Toxicologists Do?
• What toxicology is not:
– PR;
– Sales;
– Advertising;
– Lobbying;
– Spin doctoring;
– Absolute guarantors of regulatory approval;
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7. What Do Regulatory Toxicologists Do?
There is no such thing as “safe”
There are safety properties and probabilities.
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8. 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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9. The Jungle in Which Regulatory Toxicologists Live
• 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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11. The Jungle in Which Regulatory Toxicologists Live
• 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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12. The Jungle in Which Regulatory Toxicologists Live
• 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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15. The Jungle in Which Regulatory Toxicologists Live
• 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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16. The Jungle in Which Regulatory Toxicologists Live
• 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;
Dr R. B. Cope 16

17. The Jungle in Which Regulatory Toxicologists Live
• 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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18. 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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19. Factor 1 = Dread;
Factor 2 = “Control”; capacity to perceive and avoid the hazard
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20. The Jungle in Which Regulatory Toxicologists Live
• 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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23. The Jungle in Which Regulatory Toxicologists Live
• 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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24. The Jungle in Which Regulatory Toxicologists Live
• 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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27. The Jungle in Which Regulatory Toxicologists Live
• 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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28. The Jungle in Which Regulatory Toxicologists Live
• 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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29. The Jungle in Which Regulatory Toxicologists Live
• 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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30. 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,B.if ever, actually read)
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32. Orellanine from Cortinarius sp. Resembles diquat (bipyridal).
Futile redox cycling in renal tubular epithelia.
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33. Toxicological risk assessors have a key role in human
factors engineering.
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34. Do you know what this is?
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35. The consequences of misuse.
Regulatory toxicologists have little power to prevent misuse other
than risk/hazard communication (education).
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36. 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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37. Types of Regulatory Processes (High Level)
• 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 37
Dr R. B. Cope

38. Types of Regulatory Processes (High Level)
• 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).R. B. Cope
Dr 38

39. Types of Regulatory Processes (High Level)
• 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.
Dr R. B. Cope 39

40. Types of Regulatory Processes (High Level)
• 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.
Dr R. B. Cope 40

41. Types of Regulatory Processes (High Level)
• 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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42. Types of Regulatory Processes (High Level)
• 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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43. A Case Study.
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44. 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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45. 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?
Dr R. B. Cope 45

46. 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 R. B. Coperegulatory toxicologist?
Dr (d) a 46

47. 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 R. B. Coperegulatory toxicologist?
Dr
(d) a 47

48. 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? Dr R. B. Cope 48

49. 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?
Dr R. B. Cope 49

50. 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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51. If you knew that the material concerned is this?
Would you change your mind?
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52. 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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53. A Systematic Failure of a Regulatory System
• 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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54. A Systematic Failure of a Regulatory System
• 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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55. A Systematic Failure of a Regulatory System
• 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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56. 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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57. A Systematic Failure of a Regulatory System
• 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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58. 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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59. 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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63. Life is a fatal process. Most of us will not die from chemical exposure.

64. Dr R. B. Cope 64