Non-Cancer Screening Approaches for Health Effects

On this page:

• Data Hierarchy
• Screening for Non-Cancer Human Health Effects

The non-cancer screening approach provides users with a procedure of identifying health effects data for the chemical of interest from various public databases and gives insight into various chemical classes associated with health effects of concern.

Data preference hierarchy

• Experimental Data: Validated measured data from a well-designed laboratory study are always preferred.
• Analog Data: When data are not available, data on an appropriate analog may be used.
• Predicted Data: If no data on the chemical or an appropriate analog can be located, data may be predicted by appropriately using scientifically sound models.

The screening process described here can help identify the most relevant properties and effects and help determine which experimental tests may be necessary to fully characterize the chemical(s).

If experimental testing becomes neccesary to fill data gaps, then consideration should be given to the test species, route of exposure, and quality of the data.

• Information on these data review aspects can be found in the Guidelines for Pesticides and Toxic Substances.
• Relevant test guidelines include: #835 (Fate, Transport and Transformation), #850 (Ecological Effects), #870 (Health Effects), and #880 (Biochemicals).
• Additional reliable test guidelines are available from the Organization for Economic Cooperation and Development (OECD) Screening Information Data Sets (SIDS).  When characterizing potential risk of the chemical of concern, EPA's Risk Assessment Guidelines can provide information on assessing risk
• When characterizing potential risk of the chemical of concern, EPA's Risk Assessment Guidelines can provide information on assessing risk.

Screening for non-cancer human health effects

Step 1.  Locate measured data on chemical/analog

When beginning a chemical assessment, data on the following p-chem and fate properties should be located. Suggested data sources to identify this data are included in the P2 Framework Manual, and Internet searches may provide other data sources.

Information to collect

• Physical/chemical properties
• Appropriate fate transformation properties
• Biodegradation
• Media half-lives
• Metabolites/break down products
• Biochemical transformation potential
• Reaction intermediates or reaction products
• For polymers:
  • Number average molecular weight
  • Percent below MW of 500 and percent below MW of 1,000
  • MW distribution, if available
• For surfactants:
  • Cmc and krafft temperature (ambient conditions)
• For solids
  • Particle size distribution
  • Melting point

Step 2.  Determine if chemical/analog has familiar and well understood structure(s)

• Check whether chemical belongs to one of EPA's New Chemicals Program Chemical Categories.
• Polymers (high molecular weight (MW) chemicals) may not be toxic to fish as they are often too large to cross most biological membranes; however certain types of polymers may present human health concerns. EPA has concern for three types of polymers with MW >10,000. These are (a) soluble, (b) insoluble/non-water absorbing ("non-swellable"), and (c) water absorbing ("swellable"), included in Appendix F of the P2 Framework Manual.

These description of chemical classes causing local and systemic effects are for illustrative purposes, and are not intended to be comprehensive.

Chemicals causing local effects

Chemical properties/considerations relevant to eye effects include:

• Acidity
• Basicity/alkalinity
• Chemical burns (isocyanates, mustards)
• Interaction with proteins (metal salt deposition, quinones, etc.)
• Mechanical abrasions
• Solvent effects
• Surfactancy

Chemical properties/considerations relevant to rritation/corrosion to the skin:

• Acidity
• Basicity/alkalinity
• Chemical burns
• Lipophilicity
• Mechanical abrasions
• Solvent effects
• Surfactancy

Chemical properties/considerations relevant to dermal/contact sensitization:

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.

Chemical properties/considerations relevant to photo-toxicity and photosensitization:

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.

Chemical properties/considerations relevant to 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.

Chemical properties/considerations relevant to toxicity to the respiratory system:

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
• 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.

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

Compounds which can accept or lose electrons to mediate free radical formation through redox cycling include:

• Aminophenols
• Catechols, quinines, hydroquinones
• Metal complexes (iron and chromium)
• Peroxides
• Phenothiazines
• Polycyclic aromatics

Compounds that may exert toxicity through substitution for known or unknown tissue receptor ligands (receptor - mediated mechanisms) include:

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

Compounds that may exert 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.

Compounds that may exert toxicity to the kidney and are potential nephrotoxins include:

• Amines
• Certain classes of systemic drugs
• Halogenated aliphatic hydrocarbons
• Heavy metals
• Herbicides
• Insoluble salts that precipitate in the kidney (e.g., calcium complexes)
• Mycotoxins
• Organic solvents

Compounds that may manifest neurotoxicity include:

• Acids and thioacids
• Arylamide and related substances
• Acrylamides
• Alcohols
• Aliphatic halogenated hydrocarbons
• Alkanes
• Aromatic hydrocarbons
• Carbon disulfide and organic sulfur -containing compounds
• Carbon monoxide
• Catecholamines
• Certain classes of systemic drugs
• Chlorinated solvents
• Cyanide
• Cyclic halogenated hydrocarbons
• Environmental estrogens
• Ethylene oxide
• Gamma-diketones
• Inorganic nitrogenous compounds
• Isocyanates
• Ketones
• Lead
• Mercury compounds
• Metals and metalloids other than mercury and lead
• Nitriles
• Organic nitrogens
• Organophosphates
• Organophosphorus compounds
• Organotins
• Certain Pesticides
• Phenols and related substances
• Phosphorus
• Protein cross-linking agents
• Psychoactive drugs
• Pyridines (e.g., MPTP)

Compounds that may exert Immunosuppression/autoimmunity and manifest immunotoxicity include:

• Heavy metals
• Organic solvents
• Certain pesticides
• Polyhalogenated aromatic hydrocarbons

Compounds that may manifest genetic toxicity and 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
• Carbamates
• Chloramines
• Halomethanes
• Monohaloalkanes
• Multiple-ring systems
• N-methylol derivatives
• Nitrogen and sulfur mustards
• Nitroso compounds
• Propiolactones and propiosultones
• Vinyls and vinyl sulfones

Compounds that may manifest reproductive toxicity include:

• Alcohols
• Alkylating agents
• Chlorinated hydrocarbons
• Certain fungicides
• Certain herbicides
• Hydrazines
• Certain insecticides
• Metals and trace elements
• Nonylphenols
• Plastic monomers
• Solvents (e.g., glycol ethers, benzene, xylenes)
• Steroids or steroid receptor ligands

Compounds that may manifest developmental toxicity include:

• Acrylates
• Androgenic chemicals
• Anilines
• Boron containing compounds
• Chelators
• Chlorobiphenyls
• Compounds which have potential for mutagenicity and oncogenicity
• Epoxides
• Lead
• Lithium
• Mercury
• Nitrogen heterocyclic compounds
• Phthalates
• Retinoids
• Salicylates
• Short-chain branched carboxylic acid (e.g., valproic acid)
• Small benzenes
• Synthetic steroids (e.g., diethylstibesterol)
• Triazines
• Vinyl groups

Step 3.  Search online for measured data

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. The source of any data submitted should be provided to EPA with a regulatory submission to facilitate the review.

Step 4.  Use screening models, appropriately applied, to predict data

Many screening models are available that predict human health effects. Online search engines can help identify screening models to predict human health effects.

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:

• High concern
  • Evidence of adverse effects in humans
  • Conclusive evidence of severe effects in animal studies
• Moderate concern
  • Suggestive animal studies
  • Analogue data
  • Chemical class known to produce toxicity
• Low concern
  • No concern identified