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3 The Threshold of Toxicological Concern (TTC) Approach

3 The Threshold of Toxicological Concern (TTC) Approach

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334



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

Cramer

class

Class I



Class II



Class III



Description

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



13



Integrated Approaches to Testing and Assessment

Does the substance have a known structure and

are exposure data available?

Yes



335

TTC approach cannot

be applied



No



Yes



Is the substance a member of an

exclusion category? *

No

Is there a structural alert for

genotoxicity

(including metabolites)?

Low probability of

health effect

**



Yes



Exposure

> 0.0025 μg/kg bw/day?

No



Low probability of

health effect

**



No



Yes



Substance

requires non-TTC approach

(toxicity data, read-across etc.)



No

Exposure > 0.3 μg/kg bw/day? ***

Yes

Yes

Is substance an OP/Carbamate?

No

No

Exposure > 1.5 μg/kg bw/day? ***

Yes

Is substance in Cramer Class II or III?



Yes



No

No



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.



Yes



** 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).



6.4



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



336



A.P. Worth and G. Patlewicz



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

weight

of

evidence

evaluation

(http://www.regulations.

gov/#!documentDetail;D=EPA-HQ-OPPT-2010-0877-0021).

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).



7



Conclusions



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).



13



Integrated Approaches to Testing and Assessment



• pri

priority

r ori

r ty

t setti

setting

ting

• hazard

r identification

ide

d nti

t fi

f cati

t on



Integrated Approaches to

Testing and Assessment

(IATA)



337

• classification

cla

l ssifi

f cati

t on & la

llabelling

bell

lling

• risk

risk assessment

ri



Mechanistic information



Alternative Methods Toolbox



• toxicokinetic pathways

y



• in

i chemico assays

y



• Adverse

A verse Outcome Pathways

Ad

y



• in

vitro

i vi

v

tro assays

tr

y

• in

i silico

sil

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.



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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



343



344



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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