Toxicity and Assessment of Chemical Mixtures

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, potenti

Toxicity and Assessment of

Chemical Mixtures

Monday, December 12 2011

Herman Autrup

 Exposure is often to more than one chemical, either through co-exposures

EFFECTS OF MIXTURES

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?

• 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)

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)

INTERACTION TERMINOLOGY

Type of

combined effect

Subtype Synonyms Effect observed

Non-interactive Simple similar

action

Additivity Dose addition

Simple dissimilar action

Independent action

Antagonism

POTENTIATION AND ANTAGONISM

INTERACTIONS - KINETIC

• Effects on absorption, distribution,

metabolism or excretion

• Induction of ”drug” metabolizing enzymes

• Reversible inhibition of ”drug”

metabolizing enzymes (competetive or competitive)

non-• Suicide inhibition of enzymes

• Alteration in levels of co-factors

Do also apply to transporter proteins

Alteration in level of cofactors/coenzymes

Effect on protective or repair systems

Non-specific mechanisms ( cell death and damage

to membrane )

 Antagonism (of toxicological effect)

 Although this might occur is some cases, there is no public health concern

SIMPLE SIMILAR ACTION

SIMPLE SIMILAR ACTION

 Dose/concentration additivity

 It is likely to occur when the chemicals in the mixture act:

 In the same way

 By the same mechanism(s) – possibly at the same macromolecule

 Differ only in their potencies

SIMPLE SIMILAR ACTION

 Effect is obtained by summing the doses of the individual compounds, having adjusted for differences in their potencies

Effect total = Potency A x Dose A + Potency B x Dose B + + Potency N x Dose N

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 the residue is ”normalised” in term

of the reference compound

 Developed for risk assessment of

GROUPING COMPOUNDS

 Common Mechanism Group

Group of compounds having the same toxicological endpoint

 Show dose addition

 Easily defined with some groups, w.g

Anticholinesterase OPs

 More difficult with e.g Endocrine disruptors, where the effect may be similar but the mechanism different

 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

CONCENTRATION ADDITION

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 mixture

SIMPLE DISSIMILAR ACTION

DISSIMILAR ACTIONS

PROBLEM FORMULATION

 Is there environmental release

 Are the identity of at least some of the

components known

 Is there significant systemic exposure

 Is there a pausible biological hypothesis to consider the possibility of combined

effects/interactions

 Basis to consider components in ”common mechanism group

RISK ASSESSMENT PROCESS

TIERED APPROACH

 Zero tier

 Does exposure exceed relevant TTC

 First tier (e.g HI or PODI)

 Do components act on the same tissue/cell

 Same mode of action

 Plausible hypothesis for interaction

 Default factors to allow for potential synergy

HAZARD INDEX

 Hazard index (HI) is the sum of the

exposures divided by their reference doses

HI = Exposure 1 /ADI 1 + Exposure 2 /ADI 2 + + Exposure n /ADI n

 HI inappropriate as it is based on the ADI, which in turn is based upon critical NOELs

 An uncertainty factor, which may be different for the different compounds

HAZARD INDENTIFICATION

 Determine chemical composition

Chemicals in a mixture may vary

 Burning conditions in a wood stove

POTENCY APPROACH

 Hazard index (HI)

 Point of departure index (PODI)

 Toxicity equivalence factors (TEFs)

 Combined margin of exposure (MOE T )

 Cumulative risk index (CRI)

MARGIN OF EXPOSURE

 Margin of Exposure (MOE) = ED 10 /exposure

 The combined margin of exposure (MOE T ) 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

CASE STUDY (1)

 10 substances 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

CASE STUDY (2)

CASE STUDY (4)

DECISION TREE-MIXTURES

CHEMICAL AND NON-CHEMICAL STRESSORS

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 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

CONCLUSION

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.

If no mode of action information is available, the

dose/concentration addition method should be preferred over the independent action approach