Toxicity and Assessment of Chemical Mixtures

Toxicity and Assessment of Chemical Mixtures Monday, December 12 2011 Herman Autrup 1  Exposure is often to more than one chemical, either through co-exposures or exposure to mixtures  Each mixture of chemicals can have unique toxicology  Few mixtures in the real world are the same  Mixed exposures of chemicals and non-chemical stressors 2 EFFECTS OF MIXTURES 3 Is there scientific evidence that when organisms are exposed to a number of different chemical substances, that these substances may act jointly in a way (addition, antagonism, potentiation, synergies, etc.) that affects the overall level of toxicity? 4 • Substances that are mixtures themselves (multi- constituent substances, MCS; materials of unknown or variable composition, • Complex reaction products or biological materials, UVCB) • Products that contain more than one chemical e.g. cosmetics, plant protection products; • Chemicals jointly emitted from production sites, during transport processes and consumption or recycling processes; • Several chemicals that might occur together in environmental media (water, soil, air), food items, biota and humans as a result of emission from various sources and via multiple pathways. EU DG SANCO DEFINITION (2011) 5 CUMULATIVE RISK Cumulative risk means the risk of a common toxic effect associated with concurrent exposure by all relevant pathways and routes of exposure to a group of chemicals that share a common mechanism of toxicity ”Dose addition” Cumulative risk means the combined risks from aggregate exposures to multiple agents or stressors (US EPA) 6 INTERACTION TERMINOLOGY Type of combined effect Subtype Synonyms Effect observed Non-interactive Simple similar action Additivity Dose addition Simple dissimilar action Independent action Response addition Interactive Potentiation Synergy Greater than dose additive effect Antagonism Less than dose additive effects 7 Potentiation Antagonism POTENTIATION AND ANTAGONISM 8 INTERACTIONS - KINETIC • Effects on absorption, distribution, metabolism or excretion • Induction of ”drug” metabolizing enzymes • Reversible inhibition of ”drug” metabolizing enzymes (competetive or non- competitive) • Suicide inhibition of enzymes • Alteration in levels of co-factors Do also apply to transporter proteins 9 INTERACTIONS - DYNAMIC • Toxicodynamic • Changes in structure or amount of target •Up-regulation • Down-regulation • Competition Alteration in level of cofactors/coenzymes Effect on protective or repair systems Non-specific mechanisms (cell death and damage to membrane ) 10 [...]... INDENTIFICATION  Determine chemical composition Chemicals in a mixture may vary  Burning conditions in a wood stove  Predict toxicology  Test the toxicity of source-specific mixtures in animal studies Compare toxicity testing results among the various mixtures to determine which component contribute most to toxicity 25 POTENCY APPROACH  Hazard index (HI)  Point of departure index (PODI)  Toxicity equivalence... margin of exposure (MOET)  Cumulative risk index (CRI) 26 MARGIN OF EXPOSURE  Margin of Exposure (MOE) = ED10/exposure  The combined margin of exposure (MOET) is the reciprocal of the sums of the the reciprocals of the MOEs for each compound  Already widely accepted that an MOE > 100 is acceptable  The point of departure (POD) used to generate the MOE is roughly proportional to the toxicity of each... mixture = HQA + HQB + HQJ 30 CASE STUDY (4) 31 DECISION TREE -MIXTURES 32 CHEMICAL AND NON -CHEMICAL STRESSORS 33 CONCLUSION Under certain conditions, chemicals may act jointly in a way that the overall level of toxicity is being affected Chemicals with common mode of action may act jointly to produce combination effects that are larger than the effects of each mixture component applied singly These effects... Common assessment group  Group of compounds assumed to act by the same mode of action on bais of preliminary evaluation (e.g Common target organ 16 CONCENTRATION ADDITION 17 SIMPLE DISSIMILAR ACTION  Results in response addition  It occurs when: The modes, nature and/ or sites of action differ among the chemicals in the mixture The constituents do not modulate the effect of other constituents of the... action approach Interactions usually occur at medium and high dose levels (relative to the lowest effect levels) At low exposure levels, they are either not occuring or toxicologically insignificant In view of the almost infite number of possible combinations of chemicals to which humans are exposed, some form of initial filter to allow focus on mixtures of potential concern is necessary 35 ... residues is the multiplied for each member of the common mechanism group (CMG)  Thus the residue is ”normalised” in term of the reference compound  Developed for risk assessment of mixtures of structurally related dioxines 15 GROUPING COMPOUNDS  Common Mechanism Group Group of compounds having the same toxicological endpoint  Show dose addition  Easily defined with some groups, w.g Anticholinesterase... singly These effects can be described by dose/concentration additions For chemicals with different mode of action (independenly acting) no robust evidence is available that exposure to a mixture of sush substances is of health concern if the individual chemicals are present at or below their zero-effect levels 34 CONCLUSION 2 If no mode of action information is available, the dose/concentration addition... PODI)  Do components act on the same tissue/cell  Same mode of action  Plausible hypothesis for interaction  Default factors to allow for potential synergy  Second tier  Mechanism of action  Relative potency  Third tier  PBPK/PD  Probabilistic assessment of exposure and/ or hazard 23 HAZARD INDEX  Hazard index (HI) is the sum of the exposures divided by their reference doses HI = Exposure1/ADI1... Effect is obtained by summing the doses of the individual compounds, having adjusted for differences in their potencies Effecttotal = PotencyA x DoseA + PotencyB x Dose B + + PotencyN x DoseN 14 POTENCY FACTORS  Toxicity equivalence factors (TEF)  Toxicity is calculated relative to an index compound  The intake of residues is the multiplied for each member of the common mechanism group (CMG)  Thus... found in surface water  Assume all present simultaneously at all times, at max concentration detected  Assume all belong to same assessment group, i.e Dose addition  Assume 100% of drinking water is from the same source  Maximum exposure will be in children of 3-6 years of age  Exposure (mg/kg-bw/day = Surface water conc (ppm) x 0.42 L/day / 18 kg b-w 28 CASE STUDY (2) 29 CASE STUDY (3)  HQ individual . Toxicity and Assessment of Chemical Mixtures Monday, December 12 2011 Herman Autrup 1  Exposure is often to more than one chemical, either through co-exposures or exposure to mixtures . mixtures  Each mixture of chemicals can have unique toxicology  Few mixtures in the real world are the same  Mixed exposures of chemicals and non -chemical stressors 2 EFFECTS OF MIXTURES 3 Is there. associated with concurrent exposure by all relevant pathways and routes of exposure to a group of chemicals that share a common mechanism of toxicity ”Dose addition” Cumulative risk means the combined