- •CONTENTS
- •Preface
- •Contributors
- •1 Introduction to Toxicology
- •1.1 Definition and Scope, Relationship to Other Sciences, and History
- •1.1.2 Relationship to Other Sciences
- •1.1.3 A Brief History of Toxicology
- •1.3 Sources of Toxic Compounds
- •1.3.1 Exposure Classes
- •1.3.2 Use Classes
- •1.4 Movement of Toxicants in the Environment
- •Suggested Reading
- •2.1 Introduction
- •2.2 Cell Culture Techniques
- •2.2.1 Suspension Cell Culture
- •2.2.2 Monolayer Cell Culture
- •2.2.3 Indicators of Toxicity in Cultured Cells
- •2.3 Molecular Techniques
- •2.3.1 Molecular Cloning
- •2.3.2 cDNA and Genomic Libraries
- •2.3.3 Northern and Southern Blot Analyses
- •2.3.4 Polymerase Chain Reaction (PCR)
- •2.3.5 Evaluation of Gene Expression, Regulation, and Function
- •2.4 Immunochemical Techniques
- •Suggested Reading
- •3.1 Introduction
- •3.2 General Policies Related to Analytical Laboratories
- •3.2.1 Standard Operating Procedures (SOPs)
- •3.2.2 QA/QC Manuals
- •3.2.3 Procedural Manuals
- •3.2.4 Analytical Methods Files
- •3.2.5 Laboratory Information Management System (LIMS)
- •3.3 Analytical Measurement System
- •3.3.1 Analytical Instrument Calibration
- •3.3.2 Quantitation Approaches and Techniques
- •3.4 Quality Assurance (QA) Procedures
- •3.5 Quality Control (QC) Procedures
- •3.6 Summary
- •Suggested Reading
- •4 Exposure Classes, Toxicants in Air, Water, Soil, Domestic and Occupational Settings
- •4.1 Air Pollutants
- •4.1.1 History
- •4.1.2 Types of Air Pollutants
- •4.1.3 Sources of Air Pollutants
- •4.1.4 Examples of Air Pollutants
- •4.1.5 Environmental Effects
- •4.2 Water and Soil Pollutants
- •4.2.1 Sources of Water and Soil Pollutants
- •4.2.2 Examples of Pollutants
- •4.3 Occupational Toxicants
- •4.3.1 Regulation of Exposure Levels
- •4.3.2 Routes of Exposure
- •4.3.3 Examples of Industrial Toxicants
- •Suggested Reading
- •5 Classes of Toxicants: Use Classes
- •5.1 Introduction
- •5.2 Metals
- •5.2.1 History
- •5.2.2 Common Toxic Mechanisms and Sites of Action
- •5.2.3 Lead
- •5.2.4 Mercury
- •5.2.5 Cadmium
- •5.2.6 Chromium
- •5.2.7 Arsenic
- •5.2.8 Treatment of Metal Poisoning
- •5.3 Agricultural Chemicals (Pesticides)
- •5.3.1 Introduction
- •5.3.3 Organochlorine Insecticides
- •5.3.4 Organophosphorus Insecticides
- •5.3.5 Carbamate Insecticides
- •5.3.6 Botanical Insecticides
- •5.3.7 Pyrethroid Insecticides
- •5.3.8 New Insecticide Classes
- •5.3.9 Herbicides
- •5.3.10 Fungicides
- •5.3.11 Rodenticides
- •5.3.12 Fumigants
- •5.3.13 Conclusions
- •5.4 Food Additives and Contaminants
- •5.5 Toxins
- •5.5.1 History
- •5.5.2 Microbial Toxins
- •5.5.3 Mycotoxins
- •5.5.4 Algal Toxins
- •5.5.5 Plant Toxins
- •5.5.6 Animal Toxins
- •5.6 Solvents
- •5.7 Therapeutic Drugs
- •5.8 Drugs of Abuse
- •5.9 Combustion Products
- •5.10 Cosmetics
- •Suggested Reading
- •6 Absorption and Distribution of Toxicants
- •6.1 Introduction
- •6.2 Cell Membranes
- •6.3 Mechanisms of Transport
- •6.3.1 Passive Diffusion
- •6.4 Physicochemical Properties Relevant to Diffusion
- •6.4.1 Ionization
- •6.5 Routes of Absorption
- •6.5.1 Extent of Absorption
- •6.5.2 Gastrointestinal Absorption
- •6.5.3 Dermal Absorption
- •6.5.4 Respiratory Penetration
- •6.6 Toxicant Distribution
- •6.6.1 Physicochemical Properties and Protein Binding
- •6.7 Toxicokinetics
- •Suggested Reading
- •7 Metabolism of Toxicants
- •7.1 Introduction
- •7.2 Phase I Reactions
- •7.2.4 Nonmicrosomal Oxidations
- •7.2.5 Cooxidation by Cyclooxygenases
- •7.2.6 Reduction Reactions
- •7.2.7 Hydrolysis
- •7.2.8 Epoxide Hydration
- •7.2.9 DDT Dehydrochlorinase
- •7.3 Phase II Reactions
- •7.3.1 Glucuronide Conjugation
- •7.3.2 Glucoside Conjugation
- •7.3.3 Sulfate Conjugation
- •7.3.4 Methyltransferases
- •7.3.7 Acylation
- •7.3.8 Phosphate Conjugation
- •Suggested Reading
- •8 Reactive Metabolites
- •8.1 Introduction
- •8.2 Activation Enzymes
- •8.3 Nature and Stability of Reactive Metabolites
- •8.4 Fate of Reactive Metabolites
- •8.4.1 Binding to Cellular Macromolecules
- •8.4.2 Lipid Peroxidation
- •8.4.3 Trapping and Removal: Role of Glutathione
- •8.5 Factors Affecting Toxicity of Reactive Metabolites
- •8.5.1 Levels of Activating Enzymes
- •8.5.2 Levels of Conjugating Enzymes
- •8.5.3 Levels of Cofactors or Conjugating Chemicals
- •8.6 Examples of Activating Reactions
- •8.6.1 Parathion
- •8.6.2 Vinyl Chloride
- •8.6.3 Methanol
- •8.6.5 Carbon Tetrachloride
- •8.6.8 Acetaminophen
- •8.6.9 Cycasin
- •8.7 Future Developments
- •Suggested Reading
- •9.1 Introduction
- •9.2 Nutritional Effects
- •9.2.1 Protein
- •9.2.2 Carbohydrates
- •9.2.3 Lipids
- •9.2.4 Micronutrients
- •9.2.5 Starvation and Dehydration
- •9.2.6 Nutritional Requirements in Xenobiotic Metabolism
- •9.3 Physiological Effects
- •9.3.1 Development
- •9.3.2 Gender Differences
- •9.3.3 Hormones
- •9.3.4 Pregnancy
- •9.3.5 Disease
- •9.3.6 Diurnal Rhythms
- •9.4 Comparative and Genetic Effects
- •9.4.1 Variations Among Taxonomic Groups
- •9.4.2 Selectivity
- •9.4.3 Genetic Differences
- •9.5 Chemical Effects
- •9.5.1 Inhibition
- •9.5.2 Induction
- •9.5.3 Biphasic Effects: Inhibition and Induction
- •9.6 Environmental Effects
- •9.7 General Summary and Conclusions
- •Suggested Reading
- •10 Elimination of Toxicants
- •10.1 Introduction
- •10.2 Transport
- •10.3 Renal Elimination
- •10.4 Hepatic Elimination
- •10.4.2 Active Transporters of the Bile Canaliculus
- •10.5 Respiratory Elimination
- •10.6 Conclusion
- •Suggested Reading
- •11 Acute Toxicity
- •11.1 Introduction
- •11.2 Acute Exposure and Effect
- •11.3 Dose-response Relationships
- •11.4 Nonconventional Dose-response Relationships
- •11.5 Mechanisms of Acute Toxicity
- •11.5.1 Narcosis
- •11.5.2 Acetylcholinesterase Inhibition
- •11.5.3 Ion Channel Modulators
- •11.5.4 Inhibitors of Cellular Respiration
- •Suggested Reading
- •12 Chemical Carcinogenesis
- •12.1 General Aspects of Cancer
- •12.2 Human Cancer
- •12.2.1 Causes, Incidence, and Mortality Rates of Human Cancer
- •12.2.2 Known Human Carcinogens
- •12.3 Classes of Agents Associated with Carcinogenesis
- •12.3.2 Epigenetic Agents
- •12.4 General Aspects of Chemical Carcinogenesis
- •12.5 Initiation-Promotion Model for Chemical Carcinogenesis
- •12.6 Metabolic Activation of Chemical Carcinogens and DNA Adduct Formation
- •12.7 Oncogenes
- •12.8 Tumor Suppressor Genes
- •12.8.1 Inactivation of Tumor Suppressor Genes
- •12.8.2 p53 Tumor Suppressor Gene
- •12.9 General Aspects of Mutagenicity
- •12.10 Usefulness and Limitations of Mutagenicity Assays for the Identification of Carcinogens
- •Suggested Reading
- •13 Teratogenesis
- •13.1 Introduction
- •13.2 Principles of Teratology
- •13.3 Mammalian Embryology Overview
- •13.4 Critical Periods
- •13.5 Historical Teratogens
- •13.5.1 Thalidomide
- •13.5.2 Accutane (Isotetrinoin)
- •13.5.3 Diethylstilbestrol (DES)
- •13.5.4 Alcohol
- •13.6 Testing Protocols
- •13.6.1 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use
- •13.6.3 Alternative Test Methods
- •13.7 Conclusions
- •Suggested Reading
- •14 Hepatotoxicity
- •14.1 Introduction
- •14.1.1 Liver Structure
- •14.1.2 Liver Function
- •14.2 Susceptibility of the Liver
- •14.3 Types of Liver Injury
- •14.3.1 Fatty Liver
- •14.3.2 Necrosis
- •14.3.3 Apoptosis
- •14.3.4 Cholestasis
- •14.3.5 Cirrhosis
- •14.3.6 Hepatitis
- •14.3.7 Oxidative Stress
- •14.3.8 Carcinogenesis
- •14.4 Mechanisms of Hepatotoxicity
- •14.5 Examples of Hepatotoxicants
- •14.5.1 Carbon Tetrachloride
- •14.5.2 Ethanol
- •14.5.3 Bromobenzene
- •14.5.4 Acetaminophen
- •14.6 Metabolic Activation of Hepatotoxicants
- •Suggested Reading
- •15 Nephrotoxicity
- •15.1 Introduction
- •15.1.1 Structure of the Renal System
- •15.1.2 Function of the Renal System
- •15.2 Susceptibility of the Renal System
- •15.3 Examples of Nephrotoxicants
- •15.3.1 Metals
- •15.3.2 Aminoglycosides
- •15.3.3 Amphotericin B
- •15.3.4 Chloroform
- •15.3.5 Hexachlorobutadiene
- •Suggested Reading
- •16 Toxicology of the Nervous System
- •16.1 Introduction
- •16.2 The Nervous system
- •16.2.1 The Neuron
- •16.2.2 Neurotransmitters and their Receptors
- •16.2.3 Glial Cells
- •16.3 Toxicant Effects on the Nervous System
- •16.3.1 Structural Effects of Toxicants on Neurons
- •16.3.2 Effects of Toxicants on Other Cells
- •16.4 Neurotoxicity Testing
- •16.4.1 In vivo Tests of Human Exposure
- •16.4.2 In vivo Tests of Animal Exposure
- •16.4.3 In vitro Neurochemical and Histopathological End Points
- •16.5 Summary
- •Suggested Reading
- •17 Endocrine System
- •17.1 Introduction
- •17.2 Endocrine System
- •17.2.1 Nuclear Receptors
- •17.3 Endocrine Disruption
- •17.3.1 Hormone Receptor Agonists
- •17.3.2 Hormone Receptor Antagonists
- •17.3.3 Organizational versus Activational Effects of Endocrine Toxicants
- •17.3.4 Inhibitors of Hormone Synthesis
- •17.3.5 Inducers of Hormone Clearance
- •17.3.6 Hormone Displacement from Binding Proteins
- •17.4 Incidents of Endocrine Toxicity
- •17.4.1 Organizational Toxicity
- •17.4.2 Activational Toxicity
- •17.4.3 Hypothyroidism
- •17.5 Conclusion
- •Suggested Reading
- •18 Respiratory Toxicity
- •18.1 Introduction
- •18.1.1 Anatomy
- •18.1.2 Cell Types
- •18.1.3 Function
- •18.2 Susceptibility of the Respiratory System
- •18.2.1 Nasal
- •18.2.2 Lung
- •18.3 Types of Toxic Response
- •18.3.1 Irritation
- •18.3.2 Cell Necrosis
- •18.3.3 Fibrosis
- •18.3.4 Emphysema
- •18.3.5 Allergic Responses
- •18.3.6 Cancer
- •18.3.7 Mediators of Toxic Responses
- •18.4 Examples of Lung Toxicants Requiring Activation
- •18.4.1 Introduction
- •18.4.2 Monocrotaline
- •18.4.3 Ipomeanol
- •18.4.4 Paraquat
- •18.5 Defense Mechanisms
- •Suggested Reading
- •19 Immunotoxicity
- •19.1 Introduction
- •19.2 The Immune System
- •19.3 Immune Suppression
- •19.4 Classification of Immune-Mediated Injury (Hypersensitivity)
- •19.5 Effects of Chemicals on Allergic Disease
- •19.5.1 Allergic Contact Dermatitis
- •19.5.2 Respiratory Allergens
- •19.5.3 Adjuvants
- •19.6 Emerging Issues: Food Allergies, Autoimmunity, and the Developing Immune System
- •Suggested Reading
- •20 Reproductive System
- •20.1 Introduction
- •20.2 Male Reproductive Physiology
- •20.3 Mechanisms and Targets of Male Reproductive Toxicants
- •20.3.1 General Mechanisms
- •20.3.2 Effects on Germ Cells
- •20.3.3 Effects on Spermatogenesis and Sperm Quality
- •20.3.4 Effects on Sexual Behavior
- •20.3.5 Effects on Endocrine Function
- •20.4 Female Reproductive Physiology
- •20.5 Mechanisms and Targets of Female Reproductive Toxicants
- •20.5.1 Tranquilizers, Narcotics, and Social Drugs
- •20.5.2 Endocrine Disruptors (EDs)
- •20.5.3 Effects on Germ Cells
- •20.5.4 Effects on the Ovaries and Uterus
- •20.5.5 Effects on Sexual Behavior
- •Suggested Reading
- •21 Toxicity Testing
- •21.1 Introduction
- •21.2 Experimental Administration of Toxicants
- •21.2.1 Introduction
- •21.2.2 Routes of Administration
- •21.3 Chemical and Physical Properties
- •21.4 Exposure and Environmental Fate
- •21.5 In vivo Tests
- •21.5.1 Acute and Subchronic Toxicity Tests
- •21.5.2 Chronic Tests
- •21.5.3 Reproductive Toxicity and Teratogenicity
- •21.5.4 Special Tests
- •21.6 In vitro and Other Short-Term Tests
- •21.6.1 Introduction
- •21.6.2 Prokaryote Mutagenicity
- •21.6.3 Eukaryote Mutagenicity
- •21.6.4 DNA Damage and Repair
- •21.6.5 Chromosome Aberrations
- •21.6.6 Mammalian Cell Transformation
- •21.6.7 General Considerations and Testing Sequences
- •21.7 Ecological Effects
- •21.7.1 Laboratory Tests
- •21.7.2 Simulated Field Tests
- •21.7.3 Field Tests
- •21.8 Risk Analysis
- •21.9 The Future of Toxicity Testing
- •Suggested Reading
- •22 Forensic and Clinical Toxicology
- •22.1 Introduction
- •22.2 Foundations of Forensic Toxicology
- •22.3 Courtroom Testimony
- •22.4.1 Documentation Practices
- •22.4.2 Considerations for Forensic Toxicological Analysis
- •22.4.3 Drug Concentrations and Distribution
- •22.5 Laboratory Analyses
- •22.5.1 Colorimetric Screening Tests
- •22.5.2 Thermal Desorption
- •22.5.6 Enzymatic Immunoassay
- •22.6 Analytical Schemes for Toxicant Detection
- •22.7 Clinical Toxicology
- •22.7.1 History Taking
- •22.7.2 Basic Operating Rules in the Treatment of Toxicosis
- •22.7.3 Approaches to Selected Toxicoses
- •Suggested Reading
- •23 Prevention of Toxicity
- •23.1 Introduction
- •23.2 Legislation and Regulation
- •23.2.1 Federal Government
- •23.2.2 State Governments
- •23.2.3 Legislation and Regulation in Other Countries
- •23.3 Prevention in Different Environments
- •23.3.1 Home
- •23.3.2 Workplace
- •23.3.3 Pollution of Air, Water, and Land
- •23.4 Education
- •Suggested Reading
- •24 Human Health Risk Assessment
- •24.1 Introduction
- •24.2 Risk Assessment Methods
- •24.2.2 Exposure Assessment
- •24.2.3 Dose Response and Risk Characterization
- •24.3 Noncancer Risk Assessment
- •24.3.1 Default Uncertainty and Modifying Factors
- •24.3.2 Derivation of Developmental Toxicant RfD
- •24.3.3 Determination of RfD and RfC of Naphthalene with the NOAEL Approach
- •24.3.4 Benchmark Dose Approach
- •24.3.5 Determination of BMD and BMDL for ETU
- •24.3.6 Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient
- •24.3.7 Chemical Mixtures
- •24.4 Cancer Risk Assessment
- •24.5 PBPK Modeling
- •Suggested Reading
- •25 Analytical Methods in Toxicology
- •25.1 Introduction
- •25.2 Chemical and Physical Methods
- •25.2.1 Sampling
- •25.2.2 Experimental Studies
- •25.2.3 Forensic Studies
- •25.2.4 Sample Preparation
- •25.2.6 Spectroscopy
- •25.2.7 Other Analytical Methods
- •Suggested Reading
- •26 Basics of Environmental Toxicology
- •26.1 Introduction
- •26.2 Environmental Persistence
- •26.2.1 Abiotic Degradation
- •26.2.2 Biotic Degradation
- •26.2.3 Nondegradative Elimination Processes
- •26.3 Bioaccumulation
- •26.4 Toxicity
- •26.4.1 Acute Toxicity
- •26.4.2 Mechanisms of Acute Toxicity
- •26.4.3 Chronic Toxicity
- •26.4.5 Abiotic and Biotic Interactions
- •26.5 Conclusion
- •Suggested Reading
- •27.1 Introduction
- •27.2 Sources of Toxicants to the Environment
- •27.3 Transport Processes
- •27.3.1 Advection
- •27.3.2 Diffusion
- •27.4 Equilibrium Partitioning
- •27.5 Transformation Processes
- •27.5.1 Reversible Reactions
- •27.5.2 Irreversible Reactions
- •27.6 Environmental Fate Models
- •Suggested Reading
- •28 Environmental Risk Assessment
- •28.1 Introduction
- •28.2 Formulating the Problem
- •28.2.1 Selecting Assessment End Points
- •28.2.2 Developing Conceptual Models
- •28.2.3 Selecting Measures
- •28.3 Analyzing Exposure and Effects Information
- •28.3.1 Characterizing Exposure
- •28.3.2 Characterizing Ecological Effects
- •28.4 Characterizing Risk
- •28.4.1 Estimating Risk
- •28.4.2 Describing Risk
- •28.5 Managing Risk
- •Suggested Reading
- •29 Future Considerations for Environmental and Human Health
- •29.1 Introduction
- •29.2 Risk Management
- •29.3 Risk Assessment
- •29.4 Hazard and Exposure Assessment
- •29.5 In vivo Toxicity
- •29.6 In vitro Toxicity
- •29.7 Biochemical and Molecular Toxicology
- •29.8 Development of Selective Toxicants
- •Glossary
- •Index
NONCANCER RISK ASSESSMENT |
431 |
as the NOAEL approach, and it incorporates information on the sample size and shape of the dose-response curve. In fact this approach can be used for both threshold and nonthreshold adverse effects as well as continuous and quantal data sets. This requires use of Benchmark Dose Software where the dose-response is modeled and the lower confidence bound for a dose at a specified response level (benchmark response) is calculated. The benchmark response is usually specified as a 1–10% response; that is, it corresponds to a dose associated with a low level of risk such as 1–10%.
Figure 24.3 shows how an effective dose that corresponds to a specific change of effect/response (e.g., 10%) over background and a 95% lower confidence bound on the dose is calculated. The latter is often referred to as the BMDL or LBMD, as opposed to the BMD, which does not have this confidence limited associated with it.
Because the benchmark represents a statistical lower limit, larger experiments will tend, on average, to give larger benchmarks, thus rewarding good experimentation. This is not the case with NOAELs, as there is an inverse relationship between NOAEL and size of experiments. For example, poorer experiments possessing less sensitivity for detecting statistically significant increases in risk inappropriately result in higher NOAELs and RfDs, which may have an unknown unacceptable level of risk. In essence, the NOAEL is very sensitive to sample size, and there can also be high variability between experiments. With the benchmark dose approach, all the doses and slopes of the curve influence the calculations, variability of the data is considered, and the BMD is less variable between experiments. In the BMD approach quantitative toxicological data such as continuous data (organ weights serum levels, etc.) and quantal or incidence data (pathology findings, genetic anomalies, etc.) are fitted to numerous dose-response models described in the literature. The resulting benchmark dose that, for example, corresponds to a tumor risk of 10% generally can be estimated with adequate precision and not particularly dependent on the dose-response model used to fit the data. Note that dose intervals are not required for BMD estimation. This will be greatly appreciated in the cancer risk assessment section of this chapter.
24.3.5Determination of BMD and BMDL for ETU
The BMD method has been quite extensively in assessing quantal data, and very often this has involved analysis of data from developmental and reproductive toxicity
Excess fraction of |
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Upper Confidence |
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abnormal responses |
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limit on estimated risk |
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0.1 |
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Dose response fitted to experimental data
BMDL BMD |
Dose |
Figure 24.3 Benchmark dose determination from dose response relationship with the BMDL corresponding to the lower end of a one-sided 95% confidence interval for the BMD.
432 HUMAN HEALTH RISK ASSESSMENT
studies. In this study example (Crump, 1984), rats were exposed to ethylenethiourea (ETU) at 0, 5, 10, 20, 40, and 80 mg/kg doses, and the number affected with fetal anomalies per number of rats were 0/167, 0/132, 1/138, 14/81, 142/178, and 24/24, respectively. The benchmark dose computation can involve utilization of any given dose-response probability model, but in this example the quantal Weibull model was used and the specified effect was set at 0.01 (1%) with confidence level of 0.95. The BMD was determined to be 8.9 mg/kg, and the BMDL was 6.9 mg/kg. This value is close to the NOAEL, which is 5 mg/kg, but it does demonstrate that the NOAEL approximates a lower confidence limit on the BMD corresponding to an excess risk of about 1% for proportions of fetal anomalies. In fact an empirical analysis of some 486 developmental toxicity studies has demonstrated that the NOAEL can result in an excess risk of 5% for proportions of dead or malformed fetuses per litter. The reader should at this stage recognize that the BMD approach can also be used in cancer risk assessment as we are often times working with quantal data that are ideally suited for BMD modeling.
24.3.6Quantifying Risk for Noncarcinogenic Effects: Hazard Quotient
The measure used to describe the potential for noncarcinogenic toxicity to occur is not expressed as the probability. Probabilistic approach is used in cancer RA. For noncancer RA, the potential for noncarcinogenic effects is evaluated by comparing an exposure level (E) over a specified time period with a reference dose (RfD). This ratio is called a hazard quotient:
Hazard quotient = E .
RfD
In general, the greater the value of E/RfD exceeds unity, the greater is the level of concern. Note that this is a ratio and not to be interpreted as a statistical probability.
24.3.7Chemical Mixtures
Human populations are more likely to be exposed simultaneously or sequentially to a mixture of chemicals rather than to one single chemical. Standard default approaches to mixture risk assessment consider doses and responses of the mixture components to be additive. However, it should also be recognized that components in the mixture can also result in synergistic, antagonistic, or no toxicological effect following exposure to a chemical mixture. Therefore mixture toxicity cannot always be predicted even if we know the mechanisms of all toxic components in a defined mixture. Furthermore tissue dosimetry can be complicated by interactions at the route of entry (e.g., GIT, skin surface) and clearance mechanisms in the body. In essence, there are considerable uncertainties involved in trying to extrapolate effects following exposure to chemical mixtures. Several PBPK models have been used to quantitate these effects and also provide some information useful for risk assessment of chemical mixtures (Krishnan et al., 1994; Haddad et al. 2001).
The 1996 FQPA has also mandated that the EPA should also consider implementing cumulative risk assessments for pesticides. Cumulative risk assessments usually involve
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