Download - Identification of toxic substances, their biological effects ( 生物效应 ) and management of risk
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– Chemicals and Toxics– Climate Change– Emergencies– Health and Safety– Pesticides– Waste– Laws & Regulations , etc.
National Center for Biotechnology Information:
www.ncbi.nlm.nih.gov• 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 pre-market testing protocols
Benefits:• Standardized protocols (标准化 )• Comparison of toxicity• Short duration to provide resultsLimitations:• 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 damageGenetic instabilityCancer gene activation
Population responses to exposure/therapy
Why do we conduct population studies
1. Identify exposure and assess health risk2. Evaluate hazards based on reduced
exposure conditions3. Understand species and inter-individual
differences4. Identify toxicity from mixtures5. 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
• 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
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Risk Assessment Process
In 1983 the National Academy of Sciences divided the risk assessment process into 4 distinct elements:
1. Hazard identification2. Dose-response assessment3. Human exposure assessment4. 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.
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.