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Using NonCancer Screening within the SF Initiative

The Sustainable Futures / P2 Framework models predict aquatic hazard (ECOSAR and the PBT Profiler), cancer hazard potential of chemicals (OncoLogic™), and identify structures present described in EPA's Chemical Categories (PBT Profiler). As currently constructed, the Sustainable Futures / P2 Framework models do not address all biological endpoints. The "NonCancer Screening Protocol" is provided as one method for screening chemicals of concern for non-cancer health effects in the absence of data. The protocol adheres to the scientifically accepted data hierarchy, and follows that used by EPA's Risk Assessment Division in the estimation of non-cancer health effects of PreManufacture Notices (PMNs) under TSCA.

For a PDF copy of the presentation on Non-Cancer Health Effects please contact Kelly Mayo-Bean, U.S. EPA (mayo.kelly@epa.gov).

Data Hierarchy
Three stars, meaning Highest Quality: Validated measured data from a well designed laboratory study are always preferred.
two stars, meaning Analog Data: When data are not available, data on a close analog may be used. Analog must be identified by a qualified chemist.
single star, meaning Predicted Data: If no data on the chemical or the analog can be located, data may be predicted by appropriately using scientifically sound models.

If Testing Becomes Necessary

If measured data are not available, predictive models can not be used, and a decision is made to conduct testing, the screening process described here can help identify the most relevant properties, effects, and exposures, and help determine which tests may be necessary to fully characterize the chemical(s). When deciding on testing, or reviewing test data, consideration should be given to the test species, route of exposure, and quality of the data. Information on these aspects can be found in OPPTS' harmonized test guidelines developed for testing chemicals under TSCA and Federal Insecticide and Rodenticide Act (FIFRA).

Relevant test guidelines include: #835 (Fate, Transport and Transformation), #850 (Ecological Effects), #870 (Health Effects), and #880 (Biochemicals).

Additional reliable test guidelines are the Organization for Economic Cooperation and Development (OECD) Screening Information Data Sets (SIDS) Exit EPA Disclaimer. When characterizing potential risk of the chemical of concern, EPA's Risk Assessment Guidelines can provide information on assessing risk.

Screening for NonCancer Human Health Effects

STEP 1. Locate Measured Data on Chemical / Analog
Data on the following properties should be located. Suggested data sources are included in the P2 Framework Manual, and Internet searches may provide other data sources.

Physical / Chemical Properties
Fate Properties
Media half-lives
Metabolites/break down products
Biochemical Transformation Potential
Reaction intermediates or reaction products
For Polymers:
- Number average molecular weight
- % below MW of 500 and % below MW of 1,000
- MW distribution, if available

For Surfactants:
- Cmc and Krafft temperature (ambient conditions)
- For Solids
- Particle size distribution
- Melting point
- Aquatic Toxicity: Chronic and acute toxicity to fish, invertebrates, algae

STEP 2. Determine If Chemical / Analog Has Familiar and Well Understood Structure(s)

STEP 3. Search Online for Measured Data
Measured data may be available in reference or online sources. The source of any data submitted should be provided. The test species and test quality should considered as well. There are many reference and online sources of human health effects data. This web site, and the P2 Framework Manual provide reference and online data sources, however, these lists are not intended to be exhaustive. Readers are encouraged to conduct their own online searches.

STEP 4. Use Screening Models, Appropriately Applied, to Predict Data
Many screening models are available that predict human health effects. Other models exist besides those contained in Sustainable Futures / P2 Framework initiatives. Online search engines can help identify screening models to predict human health effects. An additional online aid to identifying appropriate models that predict the desired endpoints is OECD's Database on Chemical Risk Assessment Models Exit EPA Disclaimer.

Before any screening model is used, it is essential that the assessor determine the appropriateness of that specific model for evaluating the chemical(s) of concern. Not all models can evaluate all classes of chemicals. In addition, model results must be interpreted with caution. Consult the specific model's User Guide for information on appropriately using the model, and always provide the specific model used to predict the properties and effects submitted.

Once the appropriate models have been identified, and the chemical has been evaluated, the predictions should be evaluated carefully. Once this has been done, the assessor can summarize the significance of potential hazards.

STEP 5. Toxicologist Reviews Data and Estimates Concern Level
An experienced toxicologist should review the predicted data and set a concern level. Following is general guidance for setting concern levels, used by EPA in screening new chemicals under TSCA:

Chemicals Causing Local Effects
Chemicals Causing Systemic Effects
These lists of chemicals causing local and systemic effects are for illustrative purposes, and are not intended to be comprehensive.

Chemicals Causing Local Effects

[The lists provided here are for illustrative purposes, and are not intended to be comprehensive.]

Eye Effects
Chemical properties/considerations relevant to eye effects include:
Chemical burns (isocyanates, mustards)
Interaction with proteins (metal salt deposition, quinones, etc.)
Mechanical abrasions
Solvent effects

Toxicity/irritation/corrosion to the Skin
Irritation Consider:
Chemical burns
Mechanical abrasions
Solvent effects

Dermal/Contact Sensitization Consider:
Electrophilic or nucleophilic groups that could haptenize protein through covalent modification, for example: Aldehydes, ketone, codicils, quinones, other conjugated, unsaturated functional groups, epoxy groups.
Structural similarities to classes of contact allergens (parent chemical) or impurities belonging to known classes of contact allergens, for example: Antibiotics, Chlorinated antiseptics, Dyes (azo, amine), Formaldehyde releasers, Mercurials, Metals (nickel, chromium, cobalt), Natural products (plant rosins, balsams), and Preservatives.

Photo-toxicity and Photosensitization Consider:
Chemical structures that are UV absorbing (such as highly conjugated aromatics), for example: Furocoumarins, Polycyclic aromatics, and Porphyrins.
Structural similarity to systemic agents that cause photoreactions, for example: Non-steroidal anti-inflammatory agents, Sulfonamides, and Tetracyclines.

Local Toxicity to the Gastrointestinal Mucosa Consider:
Local effects in the G.I. tract will be mediated by solubility, irritation, corrosivity, and local metabolism.
For irritant and corrosive effects, consider the factors elaborated above for eye and skin.
For metabolic activation, consider the factors elaborated upon below.

Toxicity to the Respiratory System Consider:
Irritants that may cause asthma, a disease characterized by (1) airway obstruction that is reversible, (2) airway inflammation, and (3) airway hyperresponsiveness. Classes of compounds that can cause asthma include: Aldehydes, Anhydrides, Isocyanates, and Metals.
Irritant materials may cause upper airway reactivity (e.g., bronchitis)
Water soluble, reactive materials (e.g., formaldehyde) may cause nasal or upper airway toxicity an/or irritation
Particulates and fibers of a particle size that results in deep lung deposition may potentially cause chronic lung injury. Such injury is mediated by inflammatory responses, lung overload, and sustained cell turnover. Examples include: Fibers with a certain length to width ratio (e.g., asbestos), and Particulate dusts (silica, clays, talcs).
Other classes of respiratory toxicants include: Ammonia and volatile, basic amines, Isocyanates, Metal carbides, Metal oxides, Metal dusts and fumes, Nitrogen oxides, Surfactants, and Transition metals, arsenic, beryllium.

Chemicals Causing Systemic Effects

[The lists provided here are for illustrative purposes, and are not intended to be comprehensive.]

Systemic Toxicity Mediated by Intrinsic Chemical Reactivity or Biotransformation to Reactive Toxicants
Systemic organ toxicity is frequently mediated by the presence of reactive functional groups (whether present in the parent compound or introduced via biotransformation). Reactive compounds or metabolites may exert toxic effects by modification of cellular macromolecules (structural and functional cellular proteins, DNA). This can result in destruction or dysfunction of the target molecules. In addition, covalent modification of target molecules which are covalently modified may render them "foreign" or antigenic (capable of eliciting an immune response). DNA-reactive chemicals have genotoxic potential.

Toxicity Caused by Electrophiles Structural "Red flags" for chemicals containing electrophilic centers include:
Acyl halides
Aryl halides
Azides, – and S-mustards
Epoxides, strained rings (e.g., sultones)
Nitroso groups
Polarized, conjugated double bonds (e.g., quinones, a, ß unsaturated ketones, esters, nitriles)

Functional groups which undergo metabolism to electrophilic centers include:
Alkyl esters of sulfonic or phosphonic acids
Aromatic compounds with functional groups that can yield benzylic, aryl carbonium or Nitronium ions
Aromatic nitro, azo or amine groups
Conjugated aromatics that undergo epoxidation

Toxicity Caused by Free Radical Formation Compounds which can accept or lose electrons can mediate free radical formation through redox cycling.
Structural "Red flags" include:
Catechols, quinines, hydroquinones
Metal complexes (iron and chromium)
Polycyclic aromatics

Systemic Toxicity Associated with Receptor-Mediated Mechanisms Some compounds exert toxicity through substitution for known or unknown tissue receptor ligands.

Environmental estrogens (putative hormone receptor ligands)
Fibrates, phthalates (peroxisome proliferator receptor agonists)
Polychlorinated aromatics (Ah receptor ligands)
Retinoids (retinoic acid receptor ligands)

Target Organ and Functional Toxicity
Toxicity to the Liver As the primary organ of biotransformation, the liver is susceptible to toxicity mediated by chemical reactivity, as described above. Other agents with toxicity to the liver include:
Chlorinated hydrocarbons
Metals, etc.

Toxicity to the Kidney Classes of compounds that are potential nephrotoxins include:
Certain classes of systemic drugs
Halogenated aliphatic hydrocarbons
Heavy metals
Insoluble salts that precipitate in the kidney (e.g., calcium complexes)
Organic solvents

Toxicity to the Respiratory System Effects of inhaled respiratory toxicants were addressed above.

Neurotoxicity Chemicals/Classes of compounds which may manifest neurotoxicity include:
Acids and thioacids
Arylamide and related substances
Aliphatic halogenated hydrocarbons
Aromatic hydrocarbons
Carbon disulfide and organic sulfur -containing compounds
Carbon monoxide
Certain classes of systemic drugs
Chlorinated solvents
Cyclic halogenated hydrocarbons
Environmental estrogens
Ethylene oxide
Inorganic nitrogenous compounds
Mercury compounds
Metals and metalloids other than mercury and lead
Organic nitrogens
Organophosphorus compounds
Certain Pesticides
Phenols and related substances
Protein cross-linking agents
Psychoactive drugs
Pyridines (e.g., MPTP)

Immunotoxicity (Immunosuppression / Autoimmunity) Classes of compounds which may manifest immunotoxicity include:
Heavy metals
Organic solvents
Certain Pesticides
Polyhalogenated aromatic hydrocarbons

Genetic Toxicity Classes of compounds that manifest genetic toxicity are often electrophilic agents capable of modifying DNA. Such agents may act as gene mutagens, clastogens or aneugens. Compounds that can intercalate into DNA, free radical generators or chemicals that induce oxidative damage may also act as gene mutagens, clastogens or aneugens.
Mutagenic structural alerts include:
Acrylates and methacrylates
Aliphatic or aromatic nitro groups
Aliphatic or aromatic epoxides
Alkyl hydrazines
Alkyl esters of phosphonic or sulfonic acids
Alkyl aldehydes
Aromatic ring N-oxides
Aromatic azo groups
Aromatic and aliphatic aziridynyl derivatives
Aromatic alkyl amino or dialkyl amino groups
Aromatic and aliphatic substituted alkyl halides
Aromatic amines and N-hydroesters of aromatic amines
Multiple-ring systems
N-methylol derivatives
Nitrogen and sulfur mustards
Nitroso compounds
Propiolactones and propiosultones
Vinyls and vinyl sulfones

Reproductive Toxicity Classes of compounds which may manifest reproductive toxicity include:
Alkylating agents
Chlorinated hydrocarbons
Certain Fungicides
Certain Herbicides
Certain Insecticides
Metals and trace elements
Plastic monomers
Solvents (e.g., glycol ethers, benzene, xylenes)
Steroids or steroid receptor ligands

Developmental Toxicity Classes of compounds which may manifest developmental toxicity include:
Androgenic chemicals
Boron containing compounds
Compounds which have potential for mutagenicity and oncogenicity
Nitrogen Heterocyclic compounds
Short-chain branched carboxylic acid (e.g., valproic acid)
Small benzenes
Synthetic steroids (e.g., diethylstibesterol)
Vinyl groups

Blood Toxicity Classes of compounds which may manifest developmental toxicity include:
Simple aromatic amines and azo dyes that undergo azo reduction to release aromatic amines

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