Metals Toolbox

Key principles to consider in metal substances Risk Assessment (US EPA, 2007):

Key principles, defined in subsequent subsections, warrant careful consideration when assessing the risks to human health and the environment associated with exposures to metals or metal compounds and should be addressed and incorporated into metals risk assessments to the extent practicable. 

1. Metals are naturally occurring constituents in the environment and vary in concentrations across geographic regions. Implications for risk assessment include the following:

• Humans, other animals, and plants have evolved in the presence of metals and are adapted to various levels of metals. Many animals and plants exhibit geographic distributions that reflect variable requirements for and/or tolerance to certain metals.  These regional differences in requirements and tolerances should be kept in mind when conducting toxicity tests, evaluating risks, and extrapolating across regions that differ naturally in metal levels. 
• As a result of industrialisation, current levels of metals may be elevated relative to levels occurring naturally. Depending on the purpose of the risk assessment, care should be taken to understand and distinguish among naturally occurring levels, current background levels (i.e. natural and anthropogenic sources), and contributions to current levels from specific activities of concern.
• Because the diets of humans and other animals are diverse, there may be a wide variability in the dietary intake of some metals (e.g. in seafood), resulting in both temporal variability (e.g. spikes after a seafood meal or with life stage) and geographic or cultural variability.

2. All environmental media have naturally occurring mixtures of metals and metals are often introduced into the environment as mixtures. Implications for risk assessment include the following:

• Some metals act additively when they are present together, others act independently of each other, and still others are antagonistic or synergistic. Such interactions are important aspects of assessing exposure and effects. 
• Interactions among metals within organisms may occur when they compete for binding locations on specific enzymes or receptors during the processes of absorption, excretion, or sequestration, or at the target site.
• The presence and amount of other metals are important when conducting and interpreting laboratory tests.

3. Some metals are essential for maintaining proper health of humans, animals, plants, and microorganisms. Implications for risk assessment include the following:

• Adverse nutritional effects can occur if essential metals are not available in sufficient amounts. Nutritional deficits can be inherently adverse and can increase the vulnerability of humans and other organisms to other stressors, including those associated with other metals.  
• Excess amounts of essential metals can result in adverse effects if they overwhelm an organism’s homeostatic mechanisms. Such homeostatic controls do not apply at the point of contact between the organism and the environmental exposure.
• Essentiality should thus be viewed as part of the overall dose-response relationship for those metals shown to be essential, and the shape of this relationship can vary among organisms. For a given population, “reference doses” designed to protect from toxicity of excess should not be set below doses identified as essential.  Essential doses are typically life stage and gender specific.

4. The environmental chemistry of metals strongly influences their fate and effects on human and ecological Rreceptors. Unlike organic chemicals, metals are neither created nor destroyed by biological or chemical processes.  However, these processes can transform metals from one species to another (valence states) and can convert them between inorganic and organic forms.  Also, metals are present in various sizes, from small particles to large masses.  Implications for risk assessment include the following:

• The form of the metal (chemical species, compound, matrix, and particle size) influences the metal’s bioaccessibility, bioavailability, fate, and effects.
• The form of the metal is influenced by environmental properties, such as pH, particle size, moisture, redox potential, organic matter, cation exchange capacity, and acid volatile sulfides.
• Certain forms of metals are used for evaluating exposure and effects. For example, the free metal ion is used for exposure assessments based on competitive binding of metal to specific sites of action. 
• Metals attached to small airborne particles are of primary importance for inhalation exposures, although a few metals and metal compounds may exist as vapours (e.g. mercury).
• Information developed on the fate and effects of one form of a metal may not be directly applicable to other forms.
• Organometallic forms have different characteristics from inorganic metals and metal compounds, and the same general principles and approaches for risk assessment do not apply.

5. The toxicokinetics and toxicodynamics of metals depend on the metal, the form of the metal or metal Compound, and the organism’s ability to regulate and/or store the metal. These processes are often highly dynamic (e.g. vary according to exposure route and concentration, metal, and organism) and thus exert a direct influence on the expression of metal toxicity. Implications for risk assessment include the following:

• Certain metal compounds are known to bioaccumulate in tissues and this bioaccumulation can be related to their toxicity.
• The latest scientific data on bioaccumulation do not currently support the use of bioconcentration factor (BCF) and bioaccumulation factor (BAF) values when applied as generic threshold criteria for the hazard potential of inorganic metals in human and ecological risk assessment (e.g. for classification as a persistent bioaccumulative toxic [PBT] chemical).
• Single value BAFs/BCFs hold the most value for site-specific assessments when extrapolation across different exposure conditions is minimised.
• For regional and national assessments, BAFs/BCFs should be expressed as a function of media chemistry and metal concentration for particular species (or closely related organisms).
• Trophic transfer can be an important route of exposure for metals, although biomagnification of inorganic forms of metals in food webs is generally not a concern in metals assessments.
• Kinetic-based bioaccumulation models (e.g. DYNBAM) have been shown to accurately describe bioaccumulation resulting from different exposure routes for various metals and aquatic organisms and should be considered as alternatives to the BCF/BAF approach when appropriate data are available.
• Many organisms have developed physiological or anatomical means for regulating and/or storing certain metals up to certain exposure levels so that metals may not be present in organisms in a concentration, form, or place that can result in a toxic effect.
• The organ or tissue in which metal toxicity occurs may differ from the organ or tissue(s) in which the metal bioaccumulates and may be affected by the metal’s kinetics. Target organs may differ by species, mainly owing to differences in absorption, distribution, and excretion. Effects at the portal of entry to an organism are less dependent on kinetic processes internal to an organism. 
• Both the exposure route and the form of a metal can affect the metal’s carcinogenic potential (assessed in the context of human health risk assessment) and its non-cancer effects.
• Sensitivity to metals varies with age, sex, pregnancy status, nutritional status, and genetics (due to genetic polymorphisms).