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3 The Threshold of Toxicological Concern (TTC) Approach

3 The Threshold of Toxicological Concern (TTC) Approach

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A.P. Worth and G. Patlewicz

For the assessment of non-cancer endpoints, the Cramer decision tree is probably

the most commonly used approach for classifying and ranking chemicals on the

basis of their oral toxicity. It was proposed by Cramer and colleagues in 1978

(Cramer et al. 1978) as a priority setting tool and as a means of making expert judgments in food chemical safety assessment more transparent, explicit and rational,

and thus more reproducible and trustworthy. The criteria they proposed for the three

structural classes as shown in Table 13.7.

Cramer et al. (1978) based their decision tree on a series of 33 questions relating

mostly to chemical structure, but natural occurrence in food and in the body are also

taken into consideration.

Subsequently, Munro and colleagues (Munro et al. 1996) proposed the association between Cramer classes I, II and III and human exposure thresholds for noncancer endpoints of 1800, 540 and 90 μg/person/day, respectively. More recently, in

order to address all types of populations, it has been considered that the thresholds

should be expressed in μg/kg body weight (bw)/day. Based on the (historical)

assumption of a 60 kg adult, the corresponding thresholds for Cramer classes I, II and

III are 30, 9, and 1.5 μg/kg bw/day. This includes a separate TTC value (18 μg/person/day or 0.3 μg/kg bw/day) for organophosphate and carbamate neurotoxicants.

Taking into account these historical developments, along with some widely

accepted exclusion categories of chemicals for which the TTC approach is not considered applicable, EFSA subsequently published a generic scheme for the application of the TTC approach (EFSA 2012). In this Chapter, the TTC approach as

represented by the EFSA decision tree (Fig. 13.2) is regarded as an IATA—one that

integrates the use of exposure (dietary intake) information with predictions of genotoxicity, carcinogenicity, neurotoxicity, and repeat dose toxicity.

It is worth noting that the Cramer scheme was proposed in the late 1970s, before

the development of what is now understood by the TTC approach and before the

advent of computer-based tools for interpreting chemical structure and applying

structure-activity relationships. Since the original publication, the Cramer

classification scheme has been implemented into freely available software tools

such as Toxtree (Patlewicz et al. 2014; Lapenna and Worth 2011) (http://toxtree.

Table 13.7 Cramer classification scheme and associated TTC values



Class I

Class II

Class III


Substances with simple chemical structures and for

which efficient modes of metabolism exist, suggesting

a low order of oral toxicity

Substances which possess structures that are less

innocuous than class I substances, but do not contain

structural features suggestive of toxicity like those

substances in class III

Substances with chemical structures that permit no

strong initial presumption of safety or may even suggest

significant toxicity or have reactive functional groups

TTC value (μg/kg bw/day)

1800 μg/person/day

30 μg/kg bw/day

540 μg/person/day

9 μg/kg bw/day

90 μg/person/day

1.5 μg/kg bw/day


Integrated Approaches to Testing and Assessment

Does the substance have a known structure and

are exposure data available?



TTC approach cannot

be applied



Is the substance a member of an

exclusion category? *


Is there a structural alert for


(including metabolites)?

Low probability of

health effect




> 0.0025 μg/kg bw/day?


Low probability of

health effect





requires non-TTC approach

(toxicity data, read-across etc.)


Exposure > 0.3 μg/kg bw/day? ***



Is substance an OP/Carbamate?



Exposure > 1.5 μg/kg bw/day? ***


Is substance in Cramer Class II or III?




Exposure > 30 μg/kg bw/day? ***

* Exclusion categories

high potency carcinogens; inorganic substances; metals

and organometallics; proteins; steroids; substances

known/predicted to bioaccumulate; insoluble

nanomaterials; radioactive substances; mixtures.


** If exposure of infants < 6 months

is in range of TTC

→ consider if TTC is applicable

*** If exposure only short duration

→ consider margin between human

exposure & TTC value

Fig. 13.2 Generic scheme for the application of the TTC approach (reproduced with permission

from EFSA 2012)

sourceforge.net/index.html) and the OECD QSAR Toolbox (http://www.qsartoolbox.org/). Moreover, there have been various proposals in the scientific literature to

refine the TTC approach (Tluczkiewicz et al. 2011; Kalkhof et al. 2012). This is

therefore an example of an IATA which is evolving and being adapted for use in

different sectors (e.g. food, cosmetics, pesticides, chemicals).


Identification of Endocrine Active Substances

With a view to identifying substances with the potential to interact with components

of the endocrine system and, then, for substances with such potential, to identify

dose response of adverse effects for risk assessment, the U.S. Environmental

Protection Agency (EPA) launched an Endocrine Disruptor Screening Program

(EDSP) in 2009. The EDSP utilizes a two-tiered approach. The Tier 1 battery consists of five in vitro and six in vivo assays that are intended to determine the potential

of a chemical to interact with the estrogen (E), androgen (A), or thyroid (T) hormone pathways. Tier 2 is proposed to consist of multigenerational reproductive and

developmental toxicity tests in several species and is intended to determine whether

a chemical can cause adverse effects resulting from E, A, or T modulation. EDSP


A.P. Worth and G. Patlewicz

Tier 2 is not a battery—the specific Tier 2 tests required will be determined by a







Since the Tier 1 battery, as originally proposed, is expensive and time consuming

and not suitable for screening thousands of chemicals (Willett et al. 2011), efforts

are underway to develop more a cost efficient process based on in silico data (from

QSARs and Expert Systems) and HTS screening data (Reif et al. 2010; Thomas

et al. 2012; Rotroff et al. 2013; Cox et al. 2014).



The ongoing paradigm shift in toxicology from an approach in which the assessment and risk management of chemicals is based primarily on a pre-defined set of

standard and officially accepted in vivo studies to flexible, scientifically-justified

combinations (IATA) of primarily non-standard studies poses a number of intellectual and practical challenges. These challenges include the need to: (a) develop and

systemically represent knowledge of the key biokinetic and biodynamic events

involved in chemically-induced toxicity; (b) develop computational models and test

systems and IATA capable of computing or measuring these key properties and

effects; (c) design IATA that integrate such computational models and test systems

in a credible and practical way; and (d) generate sufficient evidence to convince

regulators, product stewards, and other decision makers that a given IATA is fit for

its intended purpose.

In developing integrated approaches for regulatory decision making, it is useful to

distinguish between activities aimed primarily at knowledge generation and capture;

the development and validation of models, in vitro tests and IATA; and their application in (regulatory) decision making. That said, there is inevitably an interplay

between these three activity streams (Fig. 13.3). For example, AOP development

should be regarded as an ongoing process, based on the evolving knowledge of key

events and their interrelationships with each other and adverse outcomes of interest.

Even partial knowledge of the AOP(s) underlying a given adverse outcome may be

sufficient to motivate the design of mechanistically-based IATA, which should then

be applied in order to gain practical experience. This experience will likely lead to

refinements of the IATA, for example to incorporate new components that expand the

biological and chemical applicability domains, or to recalibrate prediction models

for improved accuracy of prediction. At the same time, the practical application of

IATA should enable important knowledge gaps to be pinpointed, thereby setting the

scene for the development of tailor-made and test systems that target key mechanisms of toxicological action. Within this iterative cycle, validation of the component

parts is a key consideration, but the overriding principle is the IATA as a whole that

should be fit for purpose, and from this perspective, multiple and different solutions

could be equivalent. The role of AOPs in informing the development of IATA for

regulatory purposes is further discussed by Tollefsen et al. (2014).


Integrated Approaches to Testing and Assessment

• pri


r ori

r ty

t setti



• hazard

r identification


d nti

t fi

f cati

t on

Integrated Approaches to

Testing and Assessment



• classification


l ssifi

f cati

t on & la




• risk

risk assessment


Mechanistic information

Alternative Methods Toolbox

• toxicokinetic pathways


• in

i chemico assays


• Adverse

A verse Outcome Pathways



• in


i vi


tro assays



• in

i silico


ilico models

• chemical categories

Fig. 13.3 Generation of mechanistic knowledge and its use in guiding the development of alternative methods and design of testing strategies

The constantly shifting landscape of IATA, based not only on evolving knowledge and technologies, but on different preferences for data integration, clearly

poses a challenge for regulatory acceptance, which has traditionally been based on

the adoption of relatively fixed solutions such as test guidelines. Documenting and

communicating scientific confidence in IATA is therefore key. To address this challenge, more flexible approaches to validation and acceptance are needed. A step in

this direction has already been taken by the OECD, which through its TFHA, is

developing non-prescriptive guidance on the evaluation of Defined Approaches to

be used within IATA. If this model proves successful, it could be expanded to establish an international forum for exchanging experience on IATA, thereby facilitating,

to the extent possible, the development of harmonised approaches.

Acknowledgement The authors would like to thank Rick Becker (American Chemistry Council,

Washington DC, USA) for critically reviewing this work.


Ahlers J, Stock F, Werschkun B (2008) Integrated testing and intelligent assessment-new challenges under REACH. Environ Sci Pollut Res Int 15:565–572

Aptula AO, Roberts DW (2006) Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity. Chem

Res Toxicol 19:1097–1105

Aptula AO, Patlewicz G, Roberts DW, Schultz TW (2006) Non-enzymatic glutathione reactivity

and in vitro toxicity: a non-animal approach to skin sensitization. Toxicol In Vitro 20:239–247

Becker RA, Simon T, Patlewicz G, Kennedy SW, Farhat A, Budinsky R (2014) Improving the

development of adverse outcome pathways: lessons learned from the AhR Rodent Liver Tumor


A.P. Worth and G. Patlewicz

and AhR Avian Teratogenicity/Embryolethality AOPs. Presented at the 53rd Annual Meeting

of the Society of Toxicology, 23–27 March, 2014

Bhattacharya S, Shoda LKM, Zhang Q et al (2012) Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches. Front Physiol 3:462

Blaauboer BJ (2010) Biokinetic modeling and in vitro-in vivo extrapolations. J Toxicol Environ

Health B Crit Rev 13:242–252

Blaauboer BJ, Balls M, Bianchi V et al (1994) The ECITTS integrated toxicity testing scheme: the

application of in vitro test systems to the hazard assessment of chemicals. Toxicol In Vitro


Blaauboer B, Barratt MD, Houston JB (1999) The integrated use of alternative methods in toxicological risk evaluation. ECVAM integrated test strategies task force report 1. Altern Lab Anim


Buist H, Aldenberg T, Batke M et al (2013) The OSIRIS Weight of Evidence approach: ITS mutagenicity and ITS carcinogenicity. Regul Toxicol Pharmacol 67:170–181

Clemedson C, Kolman A, Forsby A (2007) The Integrated Acute Systemic Toxicity project

(ACuteTox) for the optimisation and validation of alternative in vitro tests. Altern Lab Anim


Council of Canadian Academies (2012) Integrating emerging technologies into chemical safety

assessment. http://www.scienceadvice.ca/en/assessments/completed/pesticides.aspx

Cox LA, Douglas D, Marty S, Rowlands JC, Patlewicz G, Goyak KO, Becker RA (2014)

Developing scientific in HTS-derived prediction models for endocrine endpoints: lessons

learned from an endocrine case study. Regul Toxicol Pharmacol 69:443–450

Cramer GM, Ford RA, Hall RL (1978) Estimation of toxic hazard—a decision tree approach. Food

Cosmet Toxicol 16:255–276

Dejongh J, Forsby A, Houston JB et al (1999) An Integrated Approach to the Prediction of Systemic

Toxicity using Computer-based Biokinetic Models and Biological In vitro Test Methods:

Overview of a Prevalidation Study Based on the ECITTS Project. Toxicol In Vitro


De Wever B, Fuchs HW, Gaca M et al (2012) Implementation challenges for designing integrated

in vitro testing strategies (ITS) aiming at reducing and replacing animal experimentation.

Toxicol In Vitro 26:526–534

Dewhurst I, Renwick AG (2013) Evaluation of the Threshold of Toxicological Concern (TTC)—

challenges and approaches. Regul Toxicol Pharmacol 65:168–177

ECHA (2012) Guidance on information requirements and chemical safety assessment. Chapter

R.7a: Endpoint specific guidance. In: Guidance for the implementation of REACH. Version 2.0.

November 2012. http://echa.europa.eu/documents/10162/13632/information_requirements_


EFSA (2012) Scientific Opinion on exploring options for providing advice about possible human

health risks based on the concept of Threshold of Toxicological Concern (TTC). EFSA

J 10(7):2750, European Food Safety Authority. http://www.efsa.europa.eu/en/efsajournal/


Emter R, Ellis G, Natsch A (2010) Performance of a novel keratinocyte-based reporter cell line to

screen skin sensitisers in vitro. Toxicol Appl Pharmacol 245:281–290

Gabbert S, van Ierland EC (2010) Cost-effectiveness analysis of chemical testing for decisionsupport: how to include animal welfare? Hum Ecol Risk Assess 16(3):603–620

Gabbert S, Weikard H-P (2013) Sequential testing of chemicals when costs matter: a value of

information approach. Hum Ecol Risk Assess An Int J 19:1067–1088

Gajewska M, Worth A, Urani C, Briesen H, Schramm K-W (2014) Application of physiologicallybased toxicokinetic modelling in oral-to-dermal extrapolation of threshold doses of cosmetic

ingredients. Toxicol Lett 227:189–202

Gerberick GF, Vassallo JD, Bailey RE et al (2004) Development of a peptide reactivity assay for

screening contact allergens. Toxicol Sci 81:332–343


Integrated Approaches to Testing and Assessment


Gerberick GF, Vassallo JD, Foertsch LM et al (2007) Quantification of chemical peptide reactivity

for screening contact allergens: a classification tree model approach. Toxicol Sci 97:417–427

Grindon C, Combes R, Cronin MTD et al (2008) Integrated testing strategies for use with respect

to the requirements of the EU REACH legislation. Altern Lab Anim 36(Suppl 1):7–27

Hartung T, Luechtefeld T, Maertens A, Kleensang A (2013) Integrated testing strategies for safety

assessments. ALTEX 30:3–18

Hennes EC (2012) An overview of values for the threshold of toxicological concern. Toxicol Lett


Hoffmann S, Kinsner-Ovaskainen A, Prieto P et al (2010) Acute oral toxicity: variability, reliability, relevance and interspecies comparison of rodent LD50 data from literature surveyed for the

ACuteTox project. Regul Toxicol Pharmacol 58:395–407

IOM (2010) Evaluation of biomarkers and surrogate endpoints in chronic disease. Institute of

Medicine, Washington, DC. ISBN 978-0-309-15129-0

Jaworska J, Hoffmann S (2010) Integrated Testing Strategy (ITS)—Opportunities to better use

existing data and guide future testing in toxicology. ALTEX 27:231–242

Jaworska J, Gabbert S, Aldenberg T (2010) Towards optimization of chemical testing under

REACH: a Bayesian network approach to Integrated Testing Strategies. Regul Toxicol

Pharmacol 57:157–167

Jaworska J, Dancik Y, Kern P et al (2013) Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice. J Appl Toxicol 33:1353–1364

Kalkhof H, Herzler M, Stahlmann R, Gundert-Remy U (2012) Threshold of toxicological concern

values for non-genotoxic effects in industrial chemicals: re-evaluation of the Cramer classification. Arch Toxicol 86:17–25

Kinsner-Ovaskainen A, Akkan Z, Casati S et al (2009) Overcoming barriers to validation of nonanimal partial replacement methods/Integrated Testing Strategies: the report of an EPAAECVAM workshop. Altern Lab Anim 37:437–444

Kinsner-Ovaskainen A, Maxwell G, Kreysa J et al (2012) Report of the EPAA-ECVAM workshop

on the validation of Integrated Testing Strategies (ITS). Altern Lab Anim 40:175–181

Lapenna S, Worth A (2011) Analysis of the Cramer classification scheme for oral systemic toxicity—implications for its implementation in Toxtree. JRC Scientific and Technical Report EUR

24898 EN. Publications Office of the European Union, Luxembourg. http://publications.jrc.


Marx-Stoelting P et al (2009) A review of the implementation of the embryonic stem cell test

(EST). The report and recommendations of an ECVAM_ReProTect Workshop. Altern Lab

Anim 37:313–328

Maxwell G, MacKay C, Cubberley R et al (2014) Applying the skin sensitisation adverse outcome

pathway (AOP) to quantitative risk assessment. Toxicol In Vitro 28:8–12

Meek ME, Boobis A, Cote I et al (2014) New developments in the evolution and application of the

WHO/IPCS framework on mode of action/species concordance analysis. J Appl Toxicol


Munro IC, Ford RA, Kennepohl E, Sprenger JG (1996) Correlation of structural class with noobserved-effect levels: a proposal for establishing a threshold of concern. Food Chem Toxicol


Norlen H, Worth AP, Gabbert S (2014) A tutorial for analysing the cost-effectiveness of alternative

methods for assessing chemical toxicity: the case of acute oral toxicity prediction. Altern Lab

Anim 42:115–127

Nukada Y, Miyazawa M, Kazutoshi S et al (2013) Data integration of non-animal tests for the

development of a test battery to predict the skin sensitizing potential and potency of chemicals.

Toxicol In Vitro 27:609–6188

Nel AE, Nasser E, Godwin H et al (2013) A multi-stakeholder perspective on the use of alternative

test strategies for nanomaterial safety assessment. ACS Nano. 7:6422–6433

NRC (2007) Toxicity testing in the 21st century: a vision and a strategy. National Academic Press,

Washington, DC. http://www.nap.edu/read/11970/chapter/1


A.P. Worth and G. Patlewicz

OECD (2002) Test No. 404: Acute Dermal Irritation/Corrosion, OECD Guidelines for the Testing

of Chemicals, Section 4. http://www.oecd.org/env/testguidelines

OECD (2007) Guidance document on the validation of (Quantitative) structure-activity relationships [(Q)SAR] models. ENV/JM/MONO(2007)2. http://www.oecd.org/officialdocuments/


OECD (2012) The adverse outcome pathway for skin sensitisation initiated by covalent binding to

proteins part 1: scientific evidence. Series on Testing and Assessment No. 168. ENV/JM/

MONO(2012)10/PART1. http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm

OECD (2013) Guidance document on developing and assessing adverse outcome pathways.

OECD Environment, Health and Safety Publications. Series on Testing and Assessment No.

184. ENV/JM/MONO(2013)6. http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm

OECD (2014a) Guidance document for describing non-guideline in vitro test methods. Series on

Testing and Assessment no.211. ENV/JM/MONO(2014)35. http://www.oecd.org/chemicalsafety/testing/seriesontestingandassessmentpublicationsbynumber.htm

OECD (2014b) How to use the Toolbox AOP workflow for Skin Sensitization. http://www.oecd.



OECD (2015a) Report of the workshop on a Framework for the development and use of Integrated

Approaches to Testing and Assessment. ENV/JM/HA(2015)1

OECD (2015b) Test Guideline 442c: in chemico skin sensitisation (Direct Peptide Reactivity

Assay DPRA). http://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.htm

OECD (2015c) Test Guideline 442d: in vitro skin sensitisation (ARE-Nrf2 luciferase test method).


OECD (2016) Guidance Document on the Reporting of Defined Approaches to be used within

Integrated Approaches to Testing and Assessment. ENV/JM/HA(2016)10

Oomen AG, Bos PMJ, Fernandes TF et al (2014) Concern-driven integrated approaches to nanomaterial testing and assessment-report of the NanoSafety Cluster Working Group 10.

Nanotoxicology 8:334–348

Patlewicz G, Simon T, Goyak K et al (2013) Use and validation of HT/HC assays to support 21st

century toxicity evaluations. Regul Toxicol Pharmacol 65:259–268

Patlewicz G, Kuseva C, Kesova A, Popova I, Zhechev T, Pavlov T, Roberts DW, Mekenyan OM

(2014) Towards AOP application—implementation of an integrated approach to testing and

assessment (IATA) into a pipeline tool for skin sensitization. Regul Toxicol Pharmacol


Patlewicz G, Simon TW, Rowlands JC, Budinsky RA, Becker RA (2015) Proposing a scientific

confidence framework to help support the application of adverse outcome pathways for regulatory purposes. Regul Toxicol Pharmacol 71:463–477

Piersma AH, Bosgra S, van Duursen MBM et al (2013) Evaluation of an alternative in vitro test

battery for detecting reproductive toxicants. Reprod Toxicol 38:53–64

Python F, Goebel C, Aeby P (2007) Assessment of the U937 cell line for the detection of contact

allergens. Toxicol Appl Pharmacol 220(2):113–124

Reif DM, Martin MT, Tan SW et al (2010) Endocrine profiling and prioritization of environmental

chemicals using ToxCast data. Environ Health Perspect 118:1714–1720

Roberts DW, Patlewicz G (2009) Chemistry based non-animal predictive modeling for skin sensitization. In: Devillers J (ed) Ecotoxicology modeling. Springer, Heidelberg, pp 61–83

Roberts DW, Patlewicz GY (2014) Integrated testing and assessment approaches for skin sensitization: a commentary. J Appl Toxicol 34(4):436–440

Roberts DW, Aptula AO, Patlewicz G, Pease C (2008) Chemical reactivity indices and mechanismbased read-across for non-animal based assessment of skin sensitisation potential. J Appl

Toxicol 28:443–454


Integrated Approaches to Testing and Assessment


Rorije E, Aldenberg T, Buist H et al (2013) The OSIRIS Weight of Evidence approach: ITS for skin

sensitisation. Regul Toxicol Pharmacol 67:146–156

Rotroff DM, Dix DJ, Houck KA, Knudsen TB, Martin MT, McLaurin KW, Reif DM, Crofton KM,

Singh AV, Xia M, Huang R, Judson RS (2013) Using in vitro high throughput screening assays

to identify potential endocrine-disrupting chemicals. Environ Health Perspect 121:7–14

Rovida C, Roggen EL (2007) Management of an Integrated Project (Sens-it-iv) to develop in vitro

tests to assess sensitisation. Altern Lab Anim 35:317–322

Rowbotham AL, Gibson RM (2011) Exposure-driven risk assessment: applying exposure-based

waiving of toxicity tests under REACH. Food Chem Toxicol 49:1661–1673

Sakaguchi H, Ashikaga T, Kosaka N, Sono S, Nishiyama N, Itagaki H (2007) The in vitro skin

sensitization test; human cell line activation test (h-CLAT) using THP-1 cells. Toxicol Letts


Schaafsma G, Kroese ED, Tielemans EL et al (2009) REACH, non-testing approaches and the

urgent need for a change in mind set. Regul Toxicol Pharmacol 53:70–80

Schultz TW, Yarbrough JW, Johnson EL (2005) Structure-activity relationships for reactivity of

carbonyl-containing compounds with glutathione. SAR QSAR Environ Res 16:313–322

Stone V, Pozzi-Mucelli S, Tran L et al (2014) ITS-NANO—Prioritising nanosafety research to

develop a stakeholder driven intelligent testing strategy. Part Fibre Toxicol 11:9

Thomas RS, Black MB, Li L, Healy E, Chu TM, Bao W, Andersen ME, Wolfinger RD (2012) A

comprehensive statistical analysis of predicting in vivo hazard using high-throughput in vitro

screening. Toxicol Sci 128:398–417

Thomas RS, Philbert MA, Auerbach SS et al (2013) Incorporating new technologies into toxicity

testing and risk assessment: moving from 21st century vision to a data-driven framework.

Toxicol Sci 136:4–18

Tluczkiewicz I, Buist HE, Martin MT et al (2011) Improvement of the Cramer classification for

oral exposure using the database TTC RepDose—a strategy description. Regul Toxicol

Pharmacol 61:340–350

Tluczkiewicz I, Batke M, Kroese D et al (2013) The OSIRIS Weight of Evidence approach: ITS

for the endpoints repeated-dose toxicity (RepDose ITS). Regul Toxicol Pharmacol


Tollefsen KE, Scholz S, Cronin MT, Edwards SW, de Knecht J, Crofton K, Garcia-Reyero N,

Hartung T, Worth A, Patlewicz G (2014) Applying Adverse Outcome Pathways (AOPs) to

support Integrated Approaches to Testing and Assessment (IATA). Regul Toxicol Pharmacol


United Nations (2013) Report of the Committee of Experts on the Transport of Dangerous Goods

and on the Globally Harmonized System of Classification and Labelling of Chemicals on its

sixth session: amendments to the fourth revised edition of the Globally Harmonized System of

Classification and Labelling of Chemicals (GHS) (ST/SG/AC.10/30/Rev.4). http://www.unece.


Van Leeuwen CJ, Patlewicz GY, Worth AP (2007) Intelligent testing strategies. In: van Leeuwen

CJ, Vermeire TG (eds) Risk assessment of chemicals. An introduction, 2nd edn. Springer,

Heidelberg, pp 467–509

Vermeire T, van de Bovenkamp M, de Bruin YB et al (2010) Exposure-based waiving under

REACH. Regul Toxicol Pharmacol 58:408–420

Vermeire T, Aldenberg T, Buist H et al (2013) OSIRIS, a quest for proof of principle for integrated

testing strategies of chemicals for four human health endpoints. Regul Toxicol Pharmacol


Willett CE, Bishop PL, Sullivan KM (2011) Application of an integrated testing strategy to the

U.S. EPA endocrine disruptor screening program. Toxicol Sci 123:15–25

Worth AP (2000) The integrated use of physicochemical and in vitro data for predicting chemical

toxicity. PhD thesis, Liverpool John Moores University

Worth AP (2004) The tiered approach to toxicity assessment based on the integrated use of alternative (non-animal) tests. In: Cronin MTD, Livingstone D (eds) Predicting chemical toxicity and

fate. CRC Press, Boca Raton, pp 389–410


A.P. Worth and G. Patlewicz

Worth AP (2010) The role of QSAR methodology in the regulatory assessment of chemicals. In:

Puzyn T, Leszczynski J, Cronin MTD (eds) Recent advances in QSAR studies: methods and

applications. Springer, Heidelberg, pp 367–382

Worth AP, Balls M (2001) The importance of the prediction model in the validation of alternative

tests. Altern Lab Anim 29:135–144

Worth AP, Cronin MT (2001) The use of bootstrap resampling to assess the variability of Draize

tissue scores. Altern Lab Anim 29:557–573

Worth AP, Fentem JH (1999) A general approach for evaluating stepwise testing strategies. Altern

Lab Anim 27:161–177

Worth AP, Fentem JH, Balls M, Botham PA, Curren RD, Earl LK, Esdaile DJ, Liebsch M (1998)

An evaluation of the proposed OECD testing strategy for skin corrosion. Altern Lab Anim


Chapter 14

International Harmonization and Cooperation

in the Validation of Alternative Methods

João Barroso, Il Young Ahn, Cristiane Caldeira, Paul L. Carmichael,

Warren Casey, Sandra Coecke, Rodger Curren, Bertrand Desprez,

Chantra Eskes, Claudius Griesinger, Jiabin Guo, Erin Hill,

Annett Janusch Roi, Hajime Kojima, Jin Li, Chae Hyung Lim,

Wlamir Moura, Akiyoshi Nishikawa, HyeKyung Park, Shuangqing Peng,

Octavio Presgrave, Tim Singer, Soo Jung Sohn, Carl Westmoreland,

Maurice Whelan, Xingfen Yang, Ying Yang and Valérie Zuang

Abstract The development and validation of scientific alternatives to animal

testing is important not only from an ethical perspective (implementation of 3Rs),

but also to improve safety assessment decision making with the use of mechanistic

information of higher relevance to humans. To be effective in these efforts, it is

however imperative that validation centres, industry, regulatory bodies, academia

and other interested parties ensure a strong international cooperation, cross-sector

collaboration and intense communication in the design, execution, and peer review

of validation studies. Such an approach is critical to achieve harmonized and more

J. Barroso (*) • S. Coecke • B. Desprez • C. Griesinger • A.J. Roi • M. Whelan • V. Zuang

European Commission, Joint Research Centre (JRC), Ispra, Italy

e-mail: joao.barroso@ec.europa.eu

I.Y. Ahn • C.H. Lim • H. Park • S.J. Sohn

Toxicological Evaluation and Research Department, Korean Center for the Validation of

Alternative Methods (KoCVAM), National Institute of Food and Drug Safety Evaluation,

Cheongju-si, South Korea

C. Caldeira • W. Moura • O. Presgrave

Brazilian Center for Validation of Alternative Methods (BraCVAM) and National Institute of

Quality Control in Health (INCQS), Rio de Janeiro, Brazil

P.L. Carmichael • J. Li • C. Westmoreland

Unilever Safety and Environmental Assurance Centre, Colworth Science Park, Sharnbrook,

Bedfordshire, UK

© Springer International Publishing Switzerland 2016

C. Eskes, M. Whelan (eds.), Validation of Alternative Methods for Toxicity Testing,

Advances in Experimental Medicine and Biology 856,

DOI 10.1007/978-3-319-33826-2_14



J. Barroso et al.

transparent approaches to method validation, peer-review and recommendation,

which will ultimately expedite the international acceptance of valid alternative

methods or strategies by regulatory authorities and their implementation and use by

stakeholders. It also allows achieving greater efficiency and effectiveness by avoiding duplication of effort and leveraging limited resources. In view of achieving

these goals, the International Cooperation on Alternative Test Methods (ICATM)

was established in 2009 by validation centres from Europe, USA, Canada and

Japan. ICATM was later joined by Korea in 2011 and currently also counts with

Brazil and China as observers. This chapter describes the existing differences across

world regions and major efforts carried out for achieving consistent international

cooperation and harmonization in the validation and adoption of alternative

approaches to animal testing.

Keywords International cooperation • Harmonization • ICATM • Validation

• Alternative methods • ECVAM • ICCVAM • NICEATM • JaCVAM • Health

Canada • KoCVAM • BraCVAM • CFDA

W. Casey

Division of the National Toxicology Program, National Institute of Environmental Health

Sciences, Research Triangle Park, DC, USA

Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM),

Washington, DC, USA

R. Curren • E. Hill

Institute for In Vitro Sciences, Inc., Gaithersburg, MD, USA

C. Eskes

Services and Consultation on Alternative Methods (SeCAM), Magliaso, Switzerland

J. Guo • S. Peng

Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention,

Academy of Military Medical Sciences, Beijing, China

H. Kojima • A. Nishikawa

Japanasese Center for the Validation of Alternative Methods (JaCVAM), National Institute of

Health Sciences, Tokyo, Japan

T. Singer

Environmental Health Science and Research Bureau, Health Canada, Ottawa, Canada

X. Yang • Y. Yang

Guangdong Province Centre for Disease Control and Prevention, Guangzhou, China

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3 The Threshold of Toxicological Concern (TTC) Approach

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