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Identification of toxic substances,
their biological effects (生物效应)
and management of risk
Topics to be addressed
• Regulatory and health agencies
• Pre-market (上市前) toxicity
evaluation
• Post-market evaluation of toxicity
and biological effects
Responsible agencies on
toxic substances
1. Regulatory agencies:
EPA (Environmental Protection Agency),
FDA (Food and Drug Administration).
3. Influenced by politics (政治), industries, and
consumer (消费者) and legal groups
4. Which agency regulates cigarette smoking?
5. Any regulations on passive exposure to
cigarette smoke?
Agencies
and their valuable websites
• International Agency for Research on
Cancer: www.iarc.fr;
• Environmental Protection Agency:
www.epa.gov
• Pubmed: www.ncbi.nlm.nih.gov
International Agency for
Research on Cancer (IARC)
• Evaluate published data from human
epidemiologic and animal studies
• Determine carcinogenic activities of chemicals,
groups of chemicals, complex mixtures (混合物),
occupational exposures, cultural habits,
biological or physical agents
IARC classifications
• Group 1 – human carcinogens: asbestos,
cigarette smoke chemicals, ionizing radiation
• Group 2A – Probable (很可能的) human
carcinogens: acrylamide, adriamycin.
• Group 2B – Possible (可能的) human
carcinogens: acetaldehyde, bleomycin, carbon
tetrachloride
• Group 3 – Not classifiable as to carcinogenic to
humans: acrylic fibers, caffeine
• Group 4 – Probably not carcinogenic to
humans
USEPA: www.epa.gov
Search: Main menu
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Chemicals and Toxics
Climate Change
Emergencies
Health and Safety
Pesticides
Waste
Laws & Regulations , etc.
National Center for
Biotechnology Information:
www.ncbi.nlm.nih.gov
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Database of Genotypes and Phenotypes (dbGaP)
Genetic Testing Registry
Influenza Virus
Online Mendelian Inheritance in Man (OMIM)
PubMed
PubMed Central (PMC)
PubMed Clinical Queries
All Genetics & Medicine Resources...
Identification of toxicity in
consumer products
• Premarket testing using standardized
protocols
• No premarket testing of natural and
some other products (Dietary
Supplements, e.g. Ginseng tablets)
• Postmarket monitoring of toxic effects in
human populations or in experimental
animals
Federal Regulations Toxicity:
Testing for a Pesticide
Acute oral, dermal and inhalation toxicity
Primary ocular and dermal irritation
Acute, delayed neurotoxicity; Dermal sensitization
21-day dermal toxicity; 90-day dermal toxicity
90-day feeding, inhalation and neurotoxicity studies
Chronic feeding study
General metabolism and domestic animal safety
Oncogenicity
Mutagenicity: Gene mutation and chromosome damage
Germ cells, reproductive and teratogenic studies
Pharmaceutical drug testing
• In vitro testing for effectiveness (有效性)
and toxicity, e.g. tumor cell lines, bacterial
cultures
• Effectiveness study in animals
• Safety and efficacy test, especially in
comparison with existing drugs
• Clinical trials in human – 3 phases: a small
group of healthy volunteers, a large group of
patients and controls, a very large group of
patients (up to 10,000)
• About 1/5000 chemicals tested became an
approved drug
Benefits and limitations of premarket testing protocols
Benefits:
• Standardized protocols (标准化)
• Comparison of toxicity
• Short duration to provide results
Limitations:
• Use of standardized cell culture or animal
• Use of high doses
• Limited test endpoints
• Very limited testing on mixtures
Postmarket testing of products
and medical activities
Chromosome damage
Genetic instability
Cancer gene activation
Population responses to
exposure/therapy
Why do we conduct population studies
1. Identify exposure and assess health risk
2. Evaluate hazards based on reduced
exposure conditions
3. Understand species and inter-individual
differences
4. Identify toxicity from mixtures
5. Provide early warning signals for
exposed populations somatic (体), germ
生殖) and embryonic (胚胎) cells (细胞)
Characteristics of
epidemiologic studies
• Provides the most useful information on
health effects from specific exposure
conditions
• Requires large sample sizes
• Insensitive to the detection of small
effects
• Does not distinguish individual variations
Biomarkers of effect with
clinical relevance
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Semen (精液) quality and sperm count
Urinary hormone assays
Pulmonary function test
Immunoglobulin (免疫球蛋白) levels
Blood lead (铅) and other chemicals
Biomarkers for subclinical
disease
1. Serum alpha-fetoprotein for liver
cancer and GI disease
2. Carcinoembryonic antigen for GI
cancers
3. Tumor specific antigen for a variety of
cancers
4. Embryonic and germ cells effects
Risk Assessment Process
In 1983 the National Academy of Sciences
divided the risk assessment process into
4 distinct elements:
1. Hazard identification
2. Dose-response assessment
3. Human exposure assessment
4. Risk characterization
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Risk Management Issues
 Risk Characterization: quantitative (定量)
vs. qualitative (定性);
 Legal Factors: uncertainty and
challenges, enforcement;
 Economic and Social Factors: impact to
industries and society;
 Public Concern: fear of harm, uncertainty
of protection, variation in response to
harm.
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Conclusions
• Understand toxicity of products and medical
activities for the prevention of health effects
• Understand susceptibility for improvement of
outcomes
• Monitor activities (post-market) for validation of
efficacy or toxicity
• Identify toxic substances and prevent human
exposure to them
• Risk characterization and management.