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.