Affiefa Yawer
C6860 Modern Methods of Pollutant Analysis


}What are toxic mixtures.
}General principal or past approach to assess toxic mixture.
}Modern approach to assess toxic mixture.
}Methodology
}Knowledge gaps
}Conclusions
}
}

}Products: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. }Emission:Chemicals jointly emitted from production sites,
during transport processes, and consumption or recycling processes. } Imissions:Several chemicals
that might occur together in environmental media (water, soil, air), food items, biota and human
tissues, as a result of emission from various sources, via multiple pathways.
}

}Metals zinc with other metals, such as copper, vanadium, nickel and iron }Dioxins, polychlorinated
biphenyls and other chlorinated hydrocarbons
}Long chained hydrocarbans with aromatic rings
}Pesticides, herbicides, fungicides
}Cosmatic products etc
}

}More than 50 years ago, three basic types of action for combinations of chemicals were defined
(Bliss 1939, Loewe and Muischnek 1926, Plackett and Hewlett 1948, Plackett and Hewlett 1952):
1-Dose/concentration addition (similarly acting chemicals)
2- independently acting chemicals
3-Interactions

}Dose/concentration addition (similarly acting chemicals): the effects can be estimated directly
from the sum of the doses/concentrations, scaled for relative toxicity
}
}
}

}Independently acting chemicals: the effects can be estimated directly from the probability of
responses to the individual components (response addition) or the sum of biological responses
(effects addition).
}pM = 1 – (1-p1) (1-p2) (1-p3)… (1-pn)
}

}Interactions:Interaction describes the combined effect of two or more chemicals as stronger
(synergistic, potentiating, supra-additive) or weaker (antagonistic, inhibitive,
subadditive,infra-additive) than would be expected on the basis of dose/concentration addition or
response addition. Interactions may therefore vary according to the relative dose levels, the
route(s), timing and duration of exposure (including the biological }persistence of the mixture
components), and the biological target(s).

}Toxicokinetic interactions; these are a common cause of deviations from additivity. Examples are
chemicals modifying the absorption of others e.g., skin penetration enhancing substances in
cosmetics. } Metabolic interactions: chemicals modifying the metabolism of other mixture
components. }Toxicodynamic interactions: interactions between the biological responses resulting
from exposure to the individual chemicals, for example resulting from similar targets (e.g.,
ligand-receptor interaction)
}Kortenkamp et al. (2009)

Fig. Schematic demonstrating the theoretical models of chemical mixture effects.



}Whole-mixture approaches: An assessment may also be based on data generated with a mixture of
reasonably similar composition or a “surrogate mixture. }If a mixture cannot be assessed in its
entirety, it may be possible to separate fractions (e.g., mixtures of petroleum hydrocarbons into
aliphatic fractions of certain chain length ranges and aromatic fractions) and to assess the
toxicities of the fractions e.g diesel exhaust (gaseous fractions and particulate matter fraction).
}Limitation: Testing whole mixtures does however not provide specific information on interactions
or the toxicity of individual mixture components.
}
}Advantage: of accounting for any unidentified materials in the mixture and for any interactions
among mixture components (Boobis et al. 2011).
}

}Component based approaches: If the components of a mixture are known, a component-based approach
is usually }performed. Information on the mode of action should be used to assess the type of
}combined action (independent action, similar action) applicable.
}

}Grouping of mixture components based on structural similarities: The chemicals in a mixture can be
grouped into assessment groups or “blocks” on the basis of their chemical structure using tools
such as the OECD (Q)SAR Application Toolbox (OECD 2009) and also according to ECHA and EFSA
guidelines.

}Dose/concentration addition approaches: Methods for dose/concentration addition approaches most
frequently used are the hazard index (HI), the reference point index (RfPI, also known as point of
departure index (PODI), the relative potency factor (RPF), or the toxic equivalency factor (TEF).

Fig. Flow chart of general guidance on the depth of toxicity data available for chemical mixtures
and appropriate risk assessment methods.


}According to WHO/IPCS 2009
}Iterative process (exposure and hazard)
}Several tiers of increasing data analysis for next step }Decision based analysis of relevant
information at early stage }Early consideration of potential for exposure compared to TCC
(Threshold of Toxicological Concern)
}Public health concern
}
}

}Under REACH regulation, some complex substances of pesticide and biocidal formulations, and
cosmetic products are considered for risk assessment. }At EU level there is currently no generally
accepted approach for the methodology to conduct a risk assessment for chemical mixtures and a
case-by-case approach is followed depending on the mixture under review. }Guidance for conducting
cumulative risk assessments has been published by the Environmental Protection Agency of the USA
(USEPA 2002), the UK Committee on }Toxicity of Chemicals in Food, Consumer Products and the
Environment (COT 2002), the }Norwegian Scientific Committee for Food Safety (VKM 2008), and the
German CVUA (CVUA 2007).

}With regard to the assessment of chemical mixtures a major knowledge gap at the present time is
the lack of knowledge on where, how often and to what extent humans and the environment are exposed
to certain chemical mixtures and how exposure may change over time.
}There is a need to better understand human and environmental exposures, both through the use of
monitoring and modeling (Tornero-Velez et al. 2011).
}For many chemicals, there is no good information on mode of action. Currently there is neither an
agreed inventory of modes of action, nor a defined set of criteria on how to characterize or
predict a mode of action for data-poor chemicals or how to group chemicals into assessment groups.
}Interactions of chemicals in mixtures are difficult to see, particularly for long-term effects.
} Research is needed to define criteria that predict potentiation or synergy.

}In ecotoxicology, the problem is even more complex. A knowledge of all possible modes of action
that may occur in the different types of organisms of a complex biological community is difficult
(if not impossible) to be attained. On the other hand, it must be considered that ecologically
relevant endpoints are generally broader and not so specific Toxicity and Assessment of Chemical
Mixtures (e.g. toxicity on specific organs, etc.) as in human toxicology. A full review of the
literature should be made to prepare a state-of-the-art on mixtures biodegradation modeling.

}Is there scientific evidence that when organisms are exposed to a number of different chemical
substances, these substances may act jointly in a way (addition, antagonism, potentiation,
synergies, etc.) that affects the overall level of toxicity? }Yes, under certain conditions,
chemicals will act jointly in a way that the overall level of toxicity is influenced. }Although
Several approaches for the assessment of the mixture effects of chemicals already exist such as
dose addition and independent action. And have their advantages and disadvantages of the different
approaches but still sufficient knowledge is required to assess chemical mixtures in a more
detailed way.

}Carlson-Lynch H, Price PS, Swartout JC, Dourson ML, Keenan RE (1999). Application of Quantitative
Information on the Uncertainty in the RfD to Noncarcinogenic Risk Assessments. Human and Ecological
Risk Assessment 5(3), 527-546. }Charles GD, Gennings C, Tornesi B, Kan HL, Zacharewski TR, Bhaskar
Gollapudi B,Carney EW (2007). Analysis of the interaction of phytoestrogens and synthetic
chemicals: an in vitro/in vivo comparison. Toxicol Appl Pharmacol. 218(3), 280-288. }Charles GD,
Gennings C, Zacharewski TR, Gollapudi BB, Carney EW (2002). An approach for assessing estrogen
receptor-mediated interactions in mixtures of three chemicals: A pilot study. Toxicol Sci. 68(2),
349-360. }Chen CL, Hsu LI, Chiou HY, Hsueh YM, Chen SY, Wu MM et al. (2004). Ingested arsenic,
cigarette smoking, and lung cancer risk: A follow-up study in arseniasisendemic areas in Taiwan.
JAMA 292, 2984-2990.

}       Altenburger R, Boedeker W, Faust M, Grimme LH (1996). Regulations for combined effects of
pollutants: consequences from risk assessment in aquatic toxicology. Foo Chem Toxicol 34, 1155-1157
} Altenburger R, Walter H, Grote M (2004). What Contributes to the Combined Effect of a Complex
Mixture? Environ Sci Technol. 38, 6353-6362 } Ankley GT, Bennett RS, Erickson RJ et al. (2010)
Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk
assessment. Environ Toxicol Chem. 2010 Mar;29(3):730-41. } ATSDR (2004). Guidance Manual for the
Assessment of Joint Toxic Action of Chemical Mixtures. US Agency for Toxic Substances and Disease
Registry. Division of Toxicology. May 2004 Bliss CI (1939). The toxicity of poisons applied
jointly. Ann Appl Biol. 26(3), 585-615. } Boobis AR, Ossendorp BC, Banasiak U, Hamey PY, Sebestyen
I, Moretto A (2008). Cumulative risk assessment of pesticide residues in food. Toxicol Lett. 180,
137-150 Boobis AR, Budinsky R, Collie S, Crofton K, Embry M, Felter S, Hertzberg R, Kopp D, Mihlan
G, Mumtaz M, Price P, Solomon K, Teuschler L, Yang R, Zaleski R (2011).
}

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