16-chemhealth.Rmd

# 化学品与健康
```{r setup, include=FALSE}
knitr::opts_chunk$set(echo = F)
```

## Chemicals in our environment: What is a chemical, and how are we exposed?

### Chemical defination

- A compound or substance that has been purified or prepared, especially artificially

### How Populations Are Exposed to Chemicals

```{r}
knitr::include_graphics("http://www.atsdr.cdc.gov/hac/PHAManual/images/figure6_2.jpg")
```

### How Chemicals Get into Our Bodies

```{r}
knitr::include_graphics("http://www.atsdr.cdc.gov/hac/PHAManual/images/figure6_3.jpg")
knitr::include_graphics("http://yufree.github.io/blogcn/figure/exposure.png")
knitr::include_graphics("http://yufree.github.io/blogcn/figure/assessment.png")
```

### Database

- [IRIS: Integrated Risk Information System (EPA)](http://www.epa.gov/iris/)

- [HazDat Database and ToxFAQ (ATSDR)](http://www.atsdr.cdc.gov/)

- [TOXNET: National Library of Medicine](http://toxnet.nlm.nih.gov/)

- [MSDS: Materials Safety Data Sheets](http://www.ccohs.ca/oshanswers/legisl/msdss.html)

### The Chemical Industry Work Environment

### Occupational Health: Understanding and Assessing Exposures and Outcomes

- Occupational Health Surveillance
- Exposure Assessment
- Occupational Epidemiology Study Designs

    - Cohort: a designated group of individuals who are identified as eligible for the study, subject to further inclusion factors, in order to evaluate factors associated with adverse health outcomes
    - no random selection of individuals into the cohort
    - Cohort studies can be prospective or retrospective
    
- What Is the Healthy Worker Effect?

    - Observation that workers exhibit lower mortality rates than the general population
    - Selection of “healthier” persons into the workforce
    - Retention of “healthier” persons in the workforce
    - In appropriate comparison population that differs in terms of Vital status ascertainment Differential diagnoses Risk factors for mortality  Access to treatment
    
### Industrial Hygiene Practices

### Regulatory Programs and Initiatives

## Toxicology: What do chemicals do in our bodies?

### Intro to Chemicals and Health

- Toxicology: the study of poisons
- Poisons: chemical or physical substances which produce adverse responses in biological organisms
- Toxicants: toxic substances that are either manmade or result from human activity
- Toxins: usually toxic substances produced by living organisms, such as reptiles, insects, plants, and microorganisms

> “The dose makes the poison” — Paracelsus

### Processes Involved in Chemical Toxicity

- Exposure is outside the body
- After absorption, you have an internal dose
- Distribution mainly through blood
    - Biotransformation
    - Elimination
    - Storage
        - Fat (lipid-soluble)
        - Bone (minerals)
- The end result of these toxicokinetic processes is a biologically effective dose (BED) of the toxicant
- The biologically effective dose is that portion of the internal dose that interacts with biological molecules (targets)
    - Leads to changes in cells 
        - Molecular
        - Biochemical changes
    - Cell toxicity
    - Organ dysfunction/disease
- The effect depends on the dose of the agent
- Toxicokinetics: (movement) processes that the body subjects the chemical to
    - Absorption: taking in of a chemical from a site(s) of exposure (i.e., gastrointestinal system) resulting in an internal dose
    - Distribution: distributing a chemical from its site of absorption throughout the body
    - Excretion/elimination: removing the chemical from the body
    - Biotransformation/metabolism: modification of chemicals by enzymes in the body
- Toxicodynamics: (changes) what the chemical does to the organism, Toxicodynamics refers to the effects of toxicants (or their metabolites) in biological systems
    - Some interactions with target molecules result in an adverse biological effect, while others may not
    - For some chemicals, the form that interacts with targets is the original chemical
    - For other chemicals, the toxic form is a biotransformation product(s) of that chemical

## Biomonitoring: How do we measure chemicals in our bodies and why?

### Exposure Assessment Approaches

- Questionnaire/historical information
- Environmental monitoring
- Personal monitoring
- Biomonitoring
- Combine these approaches with calibrated and validated models

### Biomonitoring

- A useful tool for exposure assessment
- Defined as the assessment of internal dose by measuring the parent chemical (or its metabolite or reaction product) in human specimens (for example: blood, urine)
- Measurement of concentrations, not exposures

### Evaluation of Human Exposure Using Biomonitoring

- Large–scale population surveys
    - NHANES: provides a foundation for CDC’s National Biomonitoring Program
- Epidemiological studies of specific populations
    - Susceptible/vulnerable
    - Highly exposed (for example: NICU infants, occupational settings)
    
### Considerations in Biomonitoring

- What is the best chemical measure (analyte)?
    - Parent chemical or metabolite or adduct
- What is the best time to obtain the specimen?
    - Measurement time windows
- What is the best specimen (matrix)?
    - Blood and urine
- Analytical considerations
    - Related to the specimen (for example: stability, contamination,
interferences, etc.)
    - Related to the method (for example: validated method, sensitivity, specificity, QA/QC, etc.)

### NHANES: How We Assess Exposure of the US Population to Priority Environmental Chemicals

- Began in 1971
- Continuous survey since 1999 (survey cycle = two years)
- Stratified, multistate national probability sample
- About 10,000 participants in 30 locations every two years
- method
    - Face-to-face and computer-assisted interviews:Demographics, Socioeconomic, Dietary,Health-related topics
    - Physical examination
    - Biological specimen collection
    - More at: http://www.cdc.gov/nchs/nhanes/about_nhanes.htm
- Not all chemicals are measured in everyone, except:Blood Pb, Cd, and Hg: all persons one year and older, Serum cotinine: all persons three years and older
- Most urinary chemical measurements are made in a 1/3 subsample of the participants, Ages six years and older,Subsamples are determined so they are representative of the US population
- Biomonitoring results are presented in the National Report on Human Exposure to Environmental Chemicals
- [DATA](http://www.cdc.gov/exposurereport/)
- Chemical properties (for example: persistence in the body, metabolism, stability) and analytical considerations are factors in biomarker selection and specimen collection
- Detection of a chemical does not mean that it causes disease

### Biomonitoring at the state and local laboratories

- CDC’s data can not be used at the state & local level
- [APHL. Public health laboratories](http://www.aphl.org/aboutaphl/aboutphls/pages/default.aspx)

## Health effects of chemicals: How do we figure out how chemicals affect our health?

### Discuss different types of health effects

- Acute vs latent
- Transient vs chronic
- Beneficial vs adverse

### Describe various health endpoints

- Acute toxicity
    - Generally related to short-term exposure,severeeffects
    - Example:carbonmonoxidepoisoning
    - Can have short-term and long-term consequences
- Repeated dose toxicity
    -Depends on toxicokinetics(what happens to the toxin in the body, and how quickly) 
    - Effects could be acute(threshold),subacute,orchronic
    - Example: some medications build up effects(e.g.,acetaminophen)
- Genotoxicity
    - Some chemicals can damage DNA, causing mutations when the cells divide
    - These mutations can lead to cancer if the cells are in not reproductive(eggorsperm) cells, or to some birth defects
- Carcinogenicity
    - Ability to cause cancer or make cancer more likely
    - Can be director in direct effects
    - Most chemicals that have been identified as likely carcinogens have been from animal studies; fewer from direct human epidemiology
    - Occupational workers most likely to be exposed; examples are coke oven workers, asbestos workers
- Reproductive toxicity
    - Reproduction is complex, and process can be interrupted at many points
    - Some effects from direct toxicity to egg or sperm cells, other effects on developing
    - Difficult to identify in people; most identified in animal models
fetus
- Endocrine disruption
    - Relatively recent findings of chemicals mimicking naturally occurring hormones such as sex hormones
    - Possible links to development, maturation, sexual maturation
    - Early in our understanding
- Neurotoxicity: general,delayed
    - Effect on developing or mature nervous system
    - Effects on central nervous system including cognition(lead), peripheral nervous system
- Other: immunotoxicity, allergenicity, intolerance
- [Toxicity endpoints](www.efsa.europa.eu/en/efsajournal/doc/1518.pdf)
- [National Environmental Health Tracking Network](http://ephtracking.cdc.gov)
- Causal association: Hill’s Causal Criteria

### Risk Assessment in Environmental Decision Making

- Risk Assessment
    - a policy tool designed to facilitate management of environmental health hazards
    - Risk assessment is an integration of information from various scientific domains
    - facilitate decision making, not science
- Who Uses Risk Assessment
    - Federal and international agencies
    - State environmental/health agencies
    - Industry
    - Non-governmental groups
### The Four Steps of Risk Assessment

- Hazard Identification
    - Identify chemicals of concern and potential associated health effects
    - Evaluate evidence that exposure to a given chemical elicits an adverse response
    - Qualitative evaluation of relationship between exposure and adverse effects
    - Effects seen in one human population are predictive for others
    - Average human may be as sensitive as most sensitive animal responder
    - Site concordance (tumors) or effects concordance (non-cancer responses) do not necessarily hold
- Dose-Response Assessment
    - Quantitative characterization of the relationship between a chemical agent dose and the incidence of adverse health effects
    - Where possible, quantitative toxicity metrics are presented
- Exposure Assessment
    - Quantitative characterization of human exposure/contact with chemical hazards
    - Integrates information on  Chemical concentrations in environmental media, Human activity patterns and Population characteristics
    - Predicts magnitude of human exposure in the form of external dose in milligrams per kilogram of body weight per day
    - Estimation of intake of a chemical
    - Key components Concentration of chemical in media of interest, Media intake rate, Time components(Frequency Duration Averaging time) and Body weight

```{r}
knitr::include_graphics("http://yufree.github.io/blogcn/figure/exposureM.png")
```

- Risk Characterization

    - Integration of information from hazard identification, dose-response evaluation, and exposure assessment steps
    - A risk characterization often includes ...
        - Prediction of carcinogenic risks and potential for non-carcinogenic hazard
        - Estimation of population burden (cancer)
        - Uncertainty discussion
    - Quantitative Risk Characterization
        - Risk of 1 x 10e-6 is “one case per million persons exposed over a lifetime"
    - Risk = exposed dose × effect unitless 
    - No. cases = risk × population size
    - The outputs of a risk assessment typically include an estimate of cancer risk, non- cancer hazard, population cancer burden, and an uncertainty discussion

## Chemicals policy: What do we do about chemicals and health?

### Toxic Substances Control Act

- Covers most chemicals used in industry and in commercial/consumer products
- Excludes:
    - Uses in drugs, cosmetics, food, and food packaging regulated by FDA
    - Uses in pesticides covered by EPA under FIFRA
- Basic provisions have never been amended
- Chemical Policy
    - Legislation
    - Regulation
    - Court decisions (“case law”)

### Drivers for Chemical Policy Reform

- Chemicals Are Ubiquitous
    - 10 trillion pounds produced per year in the US
    - Used to make 96% of all materials and products
    - Large but unknown number of chemicals in US commerce
- Science Drivers: Connecting the Dots
    - Certain chronic diseases are on the rise
    - Certain chemicals are linked to those same chronic diseases
    - Many of those same chemicals are in us
- Diseases Linked to Chemical Exposures
    - Cancer
    - Learning and developmental disabilities 
    - Parkinson’s and Alzheimer’s disease
    - Reproductive health and fertility problems 
    - Asthma
    - Diabetes
    - Obesity
    - Immune disorders
    - Cardiovascular disease
- Understanding of extent and pathways of chemical exposures
    - Long-range transport
    - Migration of chemicals from products into environment
    - Disproportionate exposures: environmental justice issues
    - Advent of biomonitoring
    - Early-life exposures
- Risk assessment evolution and controversy
- “RedBook”(1983),and a major update “SilverBook”(2009)
- Key challenges: Human variability, Uncertainty, Cumulative effects and exposures(Multiple chemicals, Chemicals and other stressors)
- Emerging high-throughput testing: Tox21

### Why Legislative Reform?

- New chemicals
    - No data, no problem
    - Guessing game
    - Catch-22
    - Anti-precaution
- Why Now?
    - State legislation and policy changes
    - Top priority of last two EPA administrators
    - Market demand, especially from downstream users
    - Retail regulation 
    - European Union’s REACH Regulation and Canadian Environmental Protection Act
- REACH    
    - “No data,no market”
    - Shifting the burden of proof: Industry required to show safety
    - Information flow in supply chains: Two-way flow between suppliers <--> customers
    - Authorization required to use substances of very high concern
- Action
    - [EDF](http://www.edf.org/health/policy/chemicals-policy-reform)
    - [EDF Health blog](http://blogs.edf.org/health/)