Regulatory Toxicology

Toxicology - Chaper 10 1

Regulatory Toxicology

Chapter 10


Safety evaluation& Risk Assessment

Chapter 10


Safety Evaluation

Part 1


混合


Risk Assessment

Part 2


Introduction and Definitions

Section 1


Historical context

• Advance in analytical chemistry forced the regulatory agencies to develop “tolerance levels ” such as thresholds limit values and acceptable daily intakes.

• “nondetects” are not equivalent to “not present”. There is no “absolute safe”.


Historical context

• During 20 years before 1990, only 7 substances (vinyl chloride, asbestos, benzene, radionuclides, mercury, arsenic, beryllium) had been regulated under the basis of no-effect level widely agreed as safe at that time.

• Replacement of “safety levels” with “acceptable risk levels ”.


Historical context

• NRC(1983): Risk Assessment in the Federal Government: managing the process.

• NAS(1994): Science and Judgment in Risk Assessment

• Presidential/Congresssional Commission on Risk Assessment and Risk Management (1997)


Definitions

• Risk – The probability of an adverse outcome to the human health.

• Hazard – Intrinsic toxic properties of environmental agents.

• Risk assessment – The systematic characterization of potential adverse health effects resulting from human exposure to hazardous agents or situations.


Definitions

• Risk characterization – The combination of qualitative and quantitative analysis of risk.

• Risk management – The process by which policy actions are chosen to control hazards identified in risk assessment.

• Risk communication – The challenging process of making risk assessment and management information comprehensible to community groups and “stakeholders”.


Key steps of risk assessment

Section 2


Key Steps

• Hazard identification

• Dose-response assessment

• Human exposure assessment

• Risk characterization


Risk Perception

• Knowledge

• Life experience

• Psychological factors

• Political factors

• Social and economical factors


Hazard identification

• Assessing toxicity of chemicals– Structure / activity relationship– In vitro and short-term tests– Animal bioassays– Use of epidemiologic data– Mechanistic considerations


Dose-response assessment

• Needs for extrapolations• Threshold approaches: non-carcinogenic

chemicals, system toxicants• Nonthreshold approaches: carcinogenic

chemicals, ionizing irradiation• Models derived from mechanistic assumptions


Human exposure assessment

• To determine exposure pathways• To quantify pathway-specific exposure• To calculate overall exposures

– Point estimation method– Probabilistic method


Risk characterization

• Noncancer risk calculation– NOAEL or LOAEL– RfD or RfC

• Cancer risk calculation– Radiation risk factor– Carcinogenic potency factor


Noncancer Risk Assessment

• Identify critical effect.

• Identify NOAEL or LOAEL for the critical effect.

• Apply UFs to the NOAEL or LOAEL to derive RfD or RfC.


As Defined by EPA

RfD or RfC is ...

an estimate (with uncertainty spanning perhaps an order of magnitude) of

a daily (for RfD) or continuous (for RfC) exposure to the human population (including sensitive subgroups)

that is likely to be without an appreciable risk of deleterious effects during a lifetime.


Uncertainty analysis

factors * uncertainty 10 individual difference10 or 3 difference between animal and human10 or less extrapolation from sub- to chronic10 or less extrapolation from LOAEL to NOAEL 10 or less data quality

* These factors are as used by the U.S. EPA. Other health organizations use similar factors. In EPA, the maximum UF for any given database is 3,000. Databases weaker than this are judged too uncertain to estimate RfD/RfCs.


Framework of risk assessment / management

Section 3


Risk assessment is a challenging area in toxicology

Regulatory Toxicology

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