Responsibilities of regulatory agencies; Risk assessment and risk management

What is a high production volume chemical?
It is a chemical that is produced or imported in amounts equal to or greater than one million pounds per year
What is the role of science in risk assessment?
– It investigates and attempts to explain natural phenomena. It is cautious, has to be incremental (one little step at a time), truth seeking – goal is to find out how things work
What is the role of industry in risk assessment?
It strives to develop novel compounds that will result in the greatest efficacy and safety, but also provide the largest profit margins.
What is the role of government in risk assessment?
It is the regulator, which attempts to affect human behaviour, and resolve disputes (because they concerned about public pressure)
What are the three aspects of government regulation?
episodic – when they hit something and make a decision, there’s no more going back
peremptory – the goal is to prevent problems
pursues resolution rather than truth – there is little research done, the arbitrates are based on existing data
What is the definition of risk assessment?
Where academic research, industry and government come together
Define risk assessment
The systematic scientific characterization of potential adverse health effects from human exposures.
What is risk?
It is the probability of an adverse outcome under specified conditions – it isn’t an absolute effect
What is risk management?
It is the process by which policy actions are chosen to control hazards – what you do to make sure the risk is as low as possible
What are the five objectives of risk assessment?
1. protect human and ecological health
2. balance risks and benefits
3. set target levels of risk
4. set priorities for program
5. estimate residual risks and extent of risk reduction after
What are you looking at for the protection of human and ecological health?
toxic substances
How do you balance risks and benefits?
drugs and pesticides
What do you set target levels of risk with?
food contaminants, water pollutants and rarely say a chemical can’t be used at all
How do you set priorities for program?
regulatory agencies, manufactures, environmental/consumer organizations
What is the difference between research and risk assessment?
— try to figure out how things work
— try to understand dose-response relationship, targets etc
— information from research feeds into risk assessment
Risk assessment
— people read info from research, identify things that are missing (guide for more research)
— active communication between research and risk assessment critical advancement of the field
What are the four aspects for hazard identification for risk assessment to look at?
1. Structure-activity relationships
2. In vitro and short term tests
3. Animal bioassays
4. Epidemiologic data
Aspects looked at for the structure-activity relationships?
structure, solubility, pH sensitivity, endpoints, 3D molecular modeling
What are some examples of in vitro and short term tests?
– bacterial/cell mutagenicity assays
– cell free corrosivity test
– mouse lymph node assay
– pathway based cell assay
What are some animal bioassays?
carcinogenicity (2 species, both sexes near lifetime exposure)
reproductive and developmental toxicity (don’t want to change the germline of humans)
What is some epidemiologic data looked at?
– It’s mostly correlational
Look at:
– strength of association, consistency of observations, specificity of the effect, temporal relationship, dose response, biological plausibility (link between effect X and exposure Y make sense), biomarkers
What are some epidemiologic study designs?
prospective, cohort, cross-over, double-blind study more value than a case report or case-control studies
– then you have to analyze the study and give it an intrinsic value
What are the categories to look at for a qualitative assessment of hazard information?
– consistency of data
– weight of evidence approach
– mode of action information
Where are you looking for consistency of data?
-Across species
-Target organs
How are you assessing the weight of evidence approach?
– Quantity vs quality of data (balance high quality weak signal vs low quality strong signal)
– consider all available lines of evidence
– the line of evidence is weighted depending on quality, strength of interference and relevance
What is an adverse outcome pathway? What is the goal with this?
identify toxicant, look at macromolecular interactions, cellular responses , to organ responses, to organism responses to population response
The goal is develop AOP for as many chemicals as we can to see if there are common pathways that can be viewed as key ones that are to concern when we look at new, unknown concerns
What are the four components of quantitative assessment of hazard information?
– dose response assessment
– exposure assessment
– characterization of uncertainty
– variations in suscetibility
What is a threshold for a dose response curve?
Threshold implies that the cellular mechanism exists to neutralize the toxic effect of chemical (this is the buffering capacity for toxicity)
The idea is that once you completely saturate buffering capacity, then excess chemical will start giving a toxic response
What are the two reference doses?
UF = uncertainty factor
MF = modifying factor
What is another name for a reference dose?
Rfd = ADI (acceptable daily intake)
Is there a threshold for carcinogens?
No, if shows carcinogenicity in animals, then assumed to be one in humans as well. Assume that there is no threshold
What is the Delaney- Proviso?
It is a categorical risk-benefit judgement
– no compound found “safe” as a food additive if it has been shown to cause cancer in animals or in man
How do you assess exposure?
to characterize the “distance” between expected exposures and level of exposure associated with harm, assuming there is a threshold
What are the different categories for the margin of exposure?
High MOE is good (unlikely to be exposed)
Low MOE is potentially concerning
If you are less than 1, that means you are exposed above the level associated for potential for harm
The further you are from that level, the better off you are
What are uncertainty factors?
lack of precise knowledge as to what the truth is, can be reduced through additional investigation, and it is used to account for experimental inadequacies
What are modification factors?
You can use this to adjust UFs if there is data on mechanisms, pharmacokinetics or relevance of animal response to risk are available
What are the factors involved in intraspecies and interspecies uncertainty factors?
species differences – 1 order of magnitude
there is another order of magnitude taken into account for human variability
– to be perfectly safe, you have to go 3 orders of magnitude lower than the safe level in the animal model
What is variability?
Variability refers to the heterogeneity of natural or artificial, you can’t reduce this but you can understand this by further study, so it’s outside of control
What are the steps for conducting a cumulative risk assessment?
know these steps!
What are the four steps of cumulative risk assessment?
1. select studies and endpoints
2. determine relative potency using Index Chemical
3. Determine the index Chemical’s Point of Departure or the “endpoint”
4. Risk is an integration of hazard combined with exposure
What are the 2 necessary conditions that must be established for government to act in regulating a toxicant?
1. substances must be capable of harming person who are exposed
2. humans are likely to be exposed to the substances in a way that could be harmful
Three steps for development of regulatory options?
1. control
2. substitute
3. inform
What is an information vacuum?
This is the difference between the public perception of risk and scientific assessment of risk
Different quadrants for perception of risk?
Quadrants based on observable/not observable, controllable/uncontrollable
What is the risk management framework?
problem/context –> risks –> options –> decision –> actions –> evaluations
Where do governments stop in the process?
They stop in the actions stage. The evaluation step is very expensive and time consuming.
What are the different US agencies in control?
FDA (food, drug, cosmetics)
EPA (deal with everything that has to do with the environment that affects environment and human health)
Occupational and Health Admin ( for occupational health)
Consumer Product Safety Commission (people report concerns here)
Animal Welfare Act (how animals are handled in research)
What are Canadian agencies?
1. Health Canada and Environment Canada
2. National Centre for Occupational Health and Safety
3. Canadian Council on Animal Care
What is CEPA?
It is the Canadian Environmental Protection Act
How do you define a substance as toxic?
1. if it has or may have an immediate or long term harmful effect on the environment or its biological diversity
2. constitute or may constitute a danger to the environment on which life depends
3. constitute or may constitute a danger in Canada to human life or health
4. very broad definition of what toxic substances are
What are the two factors that have to be considered in CEPA?
The weight of evidence and the precautionary principle
What is the precautionary principle?
If you don’t have enough data, you can’t use it as an excuse for not making a decision (in the case there is perceived threat, you have to analyze all of the data available)
What do some people think about the precautionary principle?
Some people think it’s flawed because in light of no data, you shouldn’t be making decisions
– you should obtain funds to do research to allow you to determine whether there is risk or not!
– the principle is used much less in the US, because they have more funds to do research than Health Canada
What is the Chemicals Management Plan?
– created by the government of canada in 2006
– CMP builds on previous initiatives to protect human health and environment by assessing chemicals used in Canada and by taking action on chemicals found to be harmful
– It also helps protect Canadians and their environment from harmful effect of chemicals substances
– People from industry and academia are provided with data on the most commonly used chemicals (they decide on prioritization, what should be done, when and how)
– This chaired by one person in academia (Which is Barbara Hales) and one person from the industry
What are the factors that regulatory decisions are based on?
Risk/benefit characterization, legislative mandage and public/political options.