identification of toxic substances, their biological effects ( 生物效应 ) and management of risk
DESCRIPTION
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?TRANSCRIPT
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Identification of toxic substances,their biological effects (生物效应 )
and management of risk
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Topics to be addressed
• Regulatory and health agencies• Pre-market (上市前 ) toxicity
evaluation• Post-market evaluation of toxicity
and biological effects
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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?
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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
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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
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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
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USEPA: www.epa.gov
Search: Main menu– Chemicals and Toxics– Climate Change– Emergencies– Health and Safety– Pesticides– Waste– Laws & Regulations , etc.
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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...
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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
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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
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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
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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
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Postmarket testing of products and medical activities
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Chromosome damageGenetic instabilityCancer gene activation
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Population responses to exposure/therapy
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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 )
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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
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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
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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.
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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.