Regulatory Toxicology and Pharmacology 58 (2010) 354–359

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Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier .com/locate /yr tph

The value of acute toxicity studies to support the clinical managementof overdose and poisoning: A cross-discipline consensus

Kathryn Chapman a,*, Stuart Creton a, Hugo Kupferschmidt b, G. Randall Bond c, Martin F. Wilks d,Sally Robinson e

a National Centre for the Replacement, Refinement and Reduction of Animals in Research, London, UKb Swiss Toxicological Information Centre (STIC), Zürich, Switzerlandc Cincinnati Drug and Poison Information Center, Cincinnati, OH, USAd Swiss Centre for Applied Human Toxicology, Basel, Switzerlande AstraZeneca, Alderley Park, UK

a r t i c l e i n f o a b s t r a c t

Article history:Received 7 May 2010Available online 11 July 2010

Keywords:Acute toxicityPharmaceuticalsChemicalsPoisoningOverdoseAnimalPreclinicalSafetyICH M3

0273-2300/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.yrtph.2010.07.003

* Corresponding author. Fax: +44 20 7670 5178.E-mail address: Kathryn.Chapman@nc3rs.org.uk (K

1 ICH M3 – International Committee on Harmonisatifor Registration of Pharmaceuticals for Human Use – T

Acute toxicity studies are no longer required to support first clinical trials of pharmaceuticals in man.However, it is unclear in the wording of the revised ICH M3 whether acute toxicity studies are requiredlater in drug development (e.g., phase 3) in order to support the management of overdose. The NC3Rsheld a workshop in January 2010 with representatives from international poison centres, the pharmaceu-tical and chemical industries, and regulatory and government bodies to explore further whether acutetoxicity studies are used to support the clinical management of overdose of pharmaceuticals and whetherthis work can be translated to other sectors such as the chemical industry. The consensus formed at theworkshop was that acute toxicity studies are not used for managing overdose of pharmaceuticals and areof little value in treating human poisoning from chemicals. In this paper, the authors describe the keyconsiderations in treating human overdose and poisoning, challenge the value of the classification andlabelling process of chemicals for this purpose and discuss how acute toxicity studies can be improvedto better inform risk assessment.1

� 2010 Elsevier Inc. All rights reserved.

1. Background

Conventional acute toxicity studies, where a single dose of acompound of up to 2000 mg/kg is administered to an animal, arethe only toxicology tests which require an estimate of lethalityas an endpoint. These studies have long been criticised on scientificgrounds (Lorke, 1983; Zbinden and Flury-Roversi, 1981), but re-main a requirement under many regulatory frameworks for chem-icals (Creton et al., 2010; Seidle et al., 2010) and until recently havealso been a core requirement for pharmaceuticals (CDER, 1996; EC,2003; ICH, 1999).

The scientific drivers for conducting acute toxicity studies inpharmaceutical development have been to select the dose for fu-ture animal studies, support the first clinical trials in humansand predict the consequences of overdose (see Fig. 1) (Robinsonet al., 2008). A review involving 18 pharmaceutical companiesand the NC3Rs has analysed the use of acute toxicity data for

ll rights reserved.

. Chapman).on of Technical Requirementsopic M3.

70 compounds across a range of therapeutic areas (Robinsonet al., 2008). This analysis demonstrated that acute toxicity stud-ies are not used to set dose levels in further animal studies or inhuman clinical trials, do not contribute to decision making aboutwhether the drug should be continued through development anddo not include parameters that may be useful to assess humansafety (e.g., target organ toxicity). As a direct result of this work,the requirement for acute toxicity data prior to first in man clin-ical trials has been removed from the ICH M3 guidelines (ICH,2009).

The non-pharmaceutical chemical industry is comprised of anumber of different sectors, including plant protection products,biocides, industrial chemicals and ingredients in consumer prod-ucts. Regulatory requirements for toxicity testing vary betweensectors, but acute systemic toxicity testing is a common require-ment for the majority of chemicals across the sectors. An exceptionto this is the cosmetics and consumer products sector: acute toxic-ity testing of cosmetic products and ingredients is now prohibitedin the EU, and is not a specific requirement in the USA or Canada. Amajor regulatory driver for conducting acute toxicity studies forchemicals is for classification and labelling according to theirpotentially hazardous properties. The information is also used tosupport elements of risk assessment and risk management such

Table 1Outline of the workshop programme.

Presentations

Do acute toxicity studies have any value in pharmaceutical development?Sally Robinson, AstraZenecaAcute toxicity studies in the chemical industry: an agrochemicals perspectiveMartin Wilks, Swiss Centre for Applied Human Toxicology, University of BaselAcute toxicity studies have little value in assessing overdoseRandall Bond, Drug and Poison Information Centre Cincinnati Children’s HospitalHow animal acute toxicity studies are used in assessing overdoseHugo Kupferschmidt, Swiss Toxicological Information CentreBreakout discussionsFeedback and conclusions

Dose settingfor other

animal studies Preclinical:

Support firstclinical trials in

humans

Supportoverdose in

humansClinical:

Fig. 1. Claimed scientific drivers for acute toxicity studies with pharmaceuticals. Anillustration of the preclinical and clinical drivers for conducting acute toxicitystudies for pharmaceuticals.

K. Chapman et al. / Regulatory Toxicology and Pharmacology 58 (2010) 354–359 355

as the setting of occupational exposure limits and chemical emer-gency response planning.

A commonly cited driver for the generation of acute toxicity dataacross pharmaceutical and chemical industry sectors is provision ofinformation to support the clinical management of accidental ordeliberate overdose or poisoning (ICCVAM-NICEATM, 2009; ICH,2009; Seidle et al., 2010; Zbinden and Flury-Roversi, 1981). In the re-vised ICH M3 guidelines for pharmaceuticals it is unclear whetherthere is a requirement for acute toxicity studies to be performed topredict the consequences of human overdose (see Box 1). The ques-tion of whether conventional acute toxicity studies are of value insupporting the clinical management of overdose or poisoning is con-troversial. High doses of a compound often elicit non-specific effectsthat may have no relevance for the human overdose situation(Chapman and Robinson, 2007; Zbinden and Flury-Roversi, 1981).Furthermore, reviews within both the pharmaceutical and chemicalindustries have highlighted that the information obtained fromacute studies is extremely limited; for instance, data on organ toxic-ity or mode of death is not obtained (Robinson et al., 2008; Seidleet al., 2010). A limited survey of Poison Centres about whether acutetoxicity data is used to assess overdose of pharmaceuticals foundthat practice differs and most Centres do not actually use the data.Those that reported using the data were actually using informationon parameters that are not normally assessed in these studies(Robinson and Chapman, 2009).

Table 2Questions discussed during the breakout sessions.

Pharmaceuticals� What data would be most valuable in assessing pharmaceutical

overdose?� Are these data provided by conventional acute toxicity studies?� Can these data be obtained from other studies carried out in pharmaceu-

tical development, e.g., safety pharmacology, repeat dose studies?� If yes, can lower doses or less severe clinical endpoints be used in these

studies?Chemicals� What data would be the most valuable in managing incidents of human

poisoning?� Is the hazard classification or occupational exposure limit of value in

managing incidents of human poisoning?� Is useful information provided by conventional acute toxicity studies?� Can this information be obtained from other studies carried out in the

chemical industry?� For studies that provide useful data, can lower doses or less severe clinical

endpoints be used to achieve the same objective?� Could these refinements be used to meet regulatory needs, i.e. classifica-

tion and labelling?

Box 1 ICH M3 recommendations on acute toxicity studiesto assess overdose. Information on the acute toxicity ofpharmaceutical agents could be useful to predict the conse-quences of human overdose situations and should be avail-able to support Phase III. An earlier assessment of acutetoxicity could be important for therapeutic indications forwhich patient populations are at higher risk for overdosing(e.g., depression, pain, and dementia) in out-patient clinicaltrials

To explore in greater detail whether data from acute toxicitystudies are used by clinicians and Poison Centres to assess andtreat human overdose and poisoning, a workshop with 25 repre-sentatives from Poison Centres, regulatory bodies and the pharma-ceutical and chemical industries was held in January 2010. Thispaper outlines and expands upon the consensus that emerged dur-ing discussions at the meeting. A list of participants is provided inthe acknowledgments.

2. Workshop format

The workshop programme is summarised in Table 1. Presenta-tions were given to review the use of acute toxicity data in the phar-

maceutical and chemical industries and how information on acutetoxicity is used in assessing human overdose and poisoning. Thesewere followed by two parallel breakout discussion sessions whereparticipants worked through a series of questions regarding the util-ity of acute toxicity data for the management of human overdose/poisoning (Table 2). Both groups discussed the same questions,and responses were fed back in a final plenary session. Participantsalso completed an individual questionnaire at the end of the meet-ing. This paper is based on the workshop presentations, feedbackfrom breakout discussions and individual questionnaire responses.

3. Results

3.1. Data required to support the management of human overdose andaccidental poisoning

Human data are of most use to Poison Centres in determininghow cases of overdose or accidental poisoning should be managedand, where available, are preferable to animal data. In terms of ani-mal data, in vivo mechanistic data are much more valuable thandata derived from acute toxicity studies. Information that wouldbe of use in managing overdose and poisoning, discussed andagreed at the workshop, is summarised in Table 3. None of thisinformation is provided by acute toxicity studies in animals, whereclinical and biochemical monitoring and gross and microscopicpathology are not usually performed.

3.2. Treatment of overdose and poisoning is not influenced by datafrom acute toxicity studies

Overdose (either deliberate or accidental) of a pharmaceuticalor chemical is treated clinically, not based on dosing. In addition,

Table 3Data of value for Poison Centres in determining how overdose and poisoning shouldbe managed, in order of preference.

Human data from clinical trials (particularly multiple and supra-therapeuticdoses)a

� Information on the pharmacological target/mode of action� Pharmacokinetics and exposure� Information on side effects and their severity (e.g., time to onset of symp-

toms and duration)

Human data after approval and marketing of drugs/chemicals

� Case reports on human overdose� Pharmaco-/Toxico vigilance data� Clinical toxicology databases (e.g., micromedex, TOXBASE, NPDS, Poison

Centre databases)� Clinical toxicology textbooks

Toxicology data from animal studies other than acute toxicityb

� Mechanism of action/toxicity� Information on adverse effects and their severity (e.g., time to onset of

symptoms, duration and recovery)� Target organ toxicity (e.g., from repeat dose toxicity studies)� Functional effects (e.g., from safety pharmacology studies)� Toxicokinetics

Physicochemical properties� pH indicative of corrosivity

a These data are not usually available for non-pharmaceutical chemicals.b In some chemical industry sectors these data may not be available, as acute

toxicity may be the only study conducted.

Table 4Acute human exposure to hazardous substances by agent classes (annual averagesfrom the Swiss Toxicological Information Centre 1998–2009, n = 272,490).

Agent group Exposures % per 100,000 population

Pharmaceuticals 9133 36.5 126.9Household chemicals 6149 24.5 85.4Plants 2721 11.0 37.8Industrial chemicals 1697 6.8 23.6Cosmetics and body care 1171 4.6 16.3Food and beverages 903 3.6 12.5Illicit and recreational drugs 883 3.5 12.3Agriculture and horticulture 744 3.0 10.3Venomous animals 417 1.7 5.8Mushrooms 401 1.6 5.6Veterinary drugs 81 0.3 1.1Other 81 2.8 9.8Total 24,772 100.0 344.1

356 K. Chapman et al. / Regulatory Toxicology and Pharmacology 58 (2010) 354–359

the reasons that data from acute toxicity studies may be of littleuse in determining treatment strategy include:

� Treatment is based on the symptoms of the patient rather thanon the doses causing toxicity in animals.� Animals are not treated for acute toxicity, and therefore situa-

tions that cause death in animals can often be prevented ortreated in humans (e.g., ventilators for respiratory depression;anti-dysrhythmics for cardiac dysrhythmia; treatment/preven-tion of kidney failure with dialysis or pre-failure preventativesupport).� Patients would be given clinical care even when previous

human experience has indicated a potential fatal outcome.� Delayed toxicity/lethality following acute exposures (as caused

by chemicals such as dimethylmercury or pharmaceuticals suchas paracetamol) may not be detected during the time course ofacute toxicity studies.� Knowledge of the dose causing lethality does not indicate how

easy or difficult it will be to treat the overdose case, or how thecase should be treated. Information on mechanism of toxicity,time to onset and whether an adverse effect is potentiallyreversible is needed to make such an assessment.

Given the limitations listed above, the simple numerical esti-mates of lethal dose provided by acute toxicity studies are not use-ful for predicting symptoms or determining how cases of poisoningshould be treated.

3.3. Different considerations between pharmaceutical and chemicalrisk assessment; the impact for acute toxicity

The class of chemicals for which cases of acute human overdoseare most frequently reported is pharmaceuticals (Table 4). How-ever, acute overexposure to chemical agents such as householdproducts, biocides, plant protection products and industrial chem-icals, as well as natural toxicants and illicit drugs, also occurs. In-deed, it has been reported that pesticide self-poisoning is themost commonly used method of suicide worldwide (Bertoloteet al., 2006; Gunnell et al., 2007).

3.3.1. Acute toxicity studies are not used for managing overdose ofpharmaceuticals

For supporting the management of overdose of pharmaceuti-cals, animal data are not required because the drug evaluation pro-cess includes human clinical trial exposure experience prior toregulatory approval and marketing.

In a small number of cases some preclinical data from animalsmay be useful, for instance, for a drug with a novel mechanismof action. Even in these cases acute toxicity studies do not provideuseful information, but other studies conducted as part of the drugdevelopment process (e.g., repeat dose toxicity and safety pharma-cology studies) do provide data that may be valuable, such as tar-get organ toxicity and functional effects.

However, as soon as one case of overdose of a novel pharmaceu-tical is reported, the preclinical and human clinical trial data, notspecifically dealing with overdose, become less valuable; knowl-edge of what happened in a human at an extremely high dose andthe outcome of any therapeutic intervention will take precedence.

3.3.2. Acute toxicity studies are of little value for treating cases ofhuman poisoning from chemicals

Information on the effects of human exposure to chemicals ismuch less widely available than for pharmaceuticals. The availabil-ity of toxicity data from animal studies differs for chemicals and isdependent on the sector. In some chemical industry sectors, suchas plant protection products and biocides, relatively extensive tox-icity testing is conducted as part of the development process, simi-lar to that for pharmaceuticals. More detailed information fromsuch studies may be helpful if there is no human experience, but re-ported human cases of intentional or accidental poisoning providethe greatest benefit for assessing overdose of these chemicals. How-ever, for some chemicals such as industrial chemicals of low pro-duction volume, acute toxicity may be the only study conducted.

The information that would be most useful for the managementof overdose/poisoning from chemicals is the same as for pharma-ceuticals (Table 3). Acute toxicity studies do not provide such dataand are not helpful for the assessment and treatment of chemicalpoisoning. Even in situations where acute toxicity is the only studyconducted and no human data are available, the absence of acutetoxicity study data would not be detrimental to clinical manage-ment decisions. If acute toxicity studies were being performed spe-cifically to provide advice on cases of human poisoning, theirconduct would not be justified.

3.4. Challenging the value of classification and labelling statements intreating poisoning

A recent survey of European chemical companies has indicatedthat the primary driver for conducting acute toxicity studies is for

K. Chapman et al. / Regulatory Toxicology and Pharmacology 58 (2010) 354–359 357

the classification and labelling of chemicals (Seidle et al., 2010).Classification for acute oral, dermal and inhalation toxicity is basedon LD50/LC50 values or range estimates of lethal doses (UN, 2009).Chemicals in classes 1–4 are considered toxic, while chemicalsconsidered ‘non-toxic’ are placed in class 5 or are unlabelled (seeTable 5). Classification and labelling is predominantly used to com-municate information on hazardous properties of chemicals so thatprotective measures can be applied during their handling, trans-port and use. However, information on acute toxicity currentlyprovided by classification and labelling is of limited value in man-aging human poisoning for several reasons:

� The hazard classification is based on lethal dose estimateswhich are of little or no value for directing treatment ofpoisoning.� The accompanying hazard and precautionary statements vary

little between category; for example, precautionary statementsfor oral toxicity in categories 1–3 all have the same advicewording (see Table 6).� Little, if any, information on appropriate treatment beyond

basic first aid measures is provided.

In addition, the hazard classification is not always a useful pre-dictor of the outcome of human poisoning. While some studies ofhuman organophosphorous pesticide (OP) poisoning have reportedreasonably good correlation between hazard class and mortality(Peter et al., 2010; Schmid et al., 2003), others have found that clas-sification does not adequately predict human toxicity. For example,a study of outcomes of human poisoning cases with three OPs allcategorised as class 2 found significant differences in severity ofsymptoms and likelihood of death between the three compounds,despite having similar LD50s in acute toxicity studies (Eddlestonet al., 2005). Even in cases where hazard class has been reportedto correlate with mortality, mortality rates are highly variable be-tween substances in a specific class; mortality rates for seven com-

Table 5GHSa acute toxicity hazard categories and LD50/LC50 criteria for classification (UN, 2009)

Exposure Route Category 1 Category 2 Category 3 Categ

Oral (mg/kg bw) 65 650 6300 6200Dermal (mg/kg bw) 650 6200 61000 6200Gases (ppm) 6100 6500 62500 620,0Vapours (mg/l) 60.5 62 610 620Dusts and mists (mg/l) 60.05 60.5 61.0 65

a GHS – Globally Harmonized System of Classification and Labelling of Chemicals.

Table 6GHSa Hazard and precautionary statements for acute oral toxicity (UN, 2009) NB: similar

Category 1 Category 2

Signal word Danger DangerHazard statement Fatal if swallowed Fatal if swallowedPrecautionary

statements(Response)

If swallowed: immediately call apoison centre or doctor/physician

If swallowed: immediatepoison centre or doctor/physician

Specific treatment (see. . .on thislabel)

Specific treatment (see. .

label)Rinse Mouth Rinse Mouth

a GHS – Globally Harmonized System of Classification and Labelling of Chemicals.

pounds in class 1 ranged from 24% to 0% in one study (Peter et al.,2010). Furthermore, the apparent linear relationship between thehazard class of organophosphates and mortality in human poison-ing reported in this study has been challenged as being an artefactof the patients’ late presentation in hospital (Eddleston, 2010).

3.5. Improved data for the treatment of chemical poisoning could alsobe used for classification and labelling

Given the limited value of acute toxicity studies for informingtreatment of chemical poisoning, it is important to assess whethermore useful information can be generated. In sectors of the chem-ical industry where additional animal toxicity studies (e.g., doserange finding, short-term and chronic toxicity and reproductivetoxicity studies) are conducted during development it should bepossible to obtain better information for the treatment of poison-ing from these studies than that currently provided by acute stud-ies. In sectors where acute toxicity may be the only systemictoxicity study performed the value of such studies could be maxi-mised by recording additional data such as clinical signs, time toonset of effects, duration, recovery rate and histopathology (toidentify target organs).

It is important to consider whether alternative study designsthat do not employ lethality as an endpoint could be used. Infor-mation on clinical signs of toxicity at doses lower than those caus-ing lethality would be of greater value in treating poisoning,particularly if parameters such as target organ toxicity are also as-sessed. Three OECD test guidelines exist for assessing acute oraltoxicity of chemicals. One of these, the fixed dose procedure(FDP), is not based on lethality but instead uses evident toxicityunder the assumption that higher doses would result more severetoxicity and/or mortality (OECD, 2001). The FDP provides a rangeestimate of the LD50 and can therefore be used for classificationand labelling and risk assessment and can provide informationon relative potency between chemicals. A similar method, the fixed

.

ory 4 Category 5

0 650000 6500000 Inhalation LC50 in the equivalent range of the oral and dermal LD50

statements are also available for acute dermal and inhalation toxicity.

Category 3 Category 4

Danger WarningToxic if swallowed Harmful if swallowed

ly call a If swallowed: immediately call apoison centre or doctor/physician

If swallowed: call a poison centreor doctor/physician if you feelunwell

.on this Specific treatment (see. . .on thislabel)Rinse Mouth Rinse Mouth

358 K. Chapman et al. / Regulatory Toxicology and Pharmacology 58 (2010) 354–359

concentration procedure (FCP), is currently under development foracute inhalation toxicity (Price et al., 2010; Stallard et al., 2010).

Regulatory requirements are the primary driver for conductingconventional acute toxicity studies. Better information on theeffects at doses lower than those causing death could meet theregulatory and scientific drivers behind acute toxicity testing andprovide better information for anticipating human toxicity. Suchinformation could also add value to classification and labelling, riskassessment and risk management.

3.6. Provision of accessible data to Poison Centres

Although acute toxicity data are not useful for assessing over-dose and poisoning, other information provided to regulatoryauthorities as part of drug and chemical development would pro-vide clinicians with valuable knowledge to make decisions ontreatment. However, these data are not readily available to clini-cians and poison centres in an accessible form. Greater availabilityand access to in vivo toxicology, clinical trial and overdose datawould be beneficial to clinicians and patients.

A co-ordinated effort to maximise knowledge from the datagenerated in drug development would involve companies and reg-ulatory agencies providing this information in an accessible form.Input from Poison Centres would also be required to help set astandard format in which these data could be provided to optimisetheir use.

2 The views expressed in this paper do not necessarily reflect those of thestitutions represented by the workshop attendees.

4. Conclusions

The workshop provided a rare and unique opportunity to gatherperspectives on the value of acute toxicity studies from a widerange of interested parties. This was the first time that representa-tives from Poison Centres, regulators and toxicologists from Europeand the US had discussed the use of animal data in supporting themanagement and treatment of overdose and poisoning in humans.A number of key conclusions were reached at the meeting:

� Acute toxicity studies do not provide information to clinicianson how to treat poisoning and overdose patients for pharma-ceutical and non-pharmaceutical chemicals.� Human data are of most value to Poison Centres in informing

treatment of overdose and poisoning.� More useful animal toxicity data could be obtained from non-

lethal studies that are already carried out as part of the productdevelopment process.� In sectors where acute toxicity may be the only systemic toxic-

ity study performed, the value of such studies could be maxi-mised by improving the design.� There is little differentiation in hazard statements and treat-

ment advice between classification and labelling categoriesand therefore this is of no value in the specific managementof poisoning.

For non-pharmaceutical chemicals the rationale for carrying outacute studies needs to be better delineated. Given the limitedinformation provided by acute toxicity studies, the authors recom-mend that experts from industry and regulatory bodies dealingwith risk assessment and risk management issues meet to recon-sider the value of acute toxicity studies and explore alternativestudies that may more effectively meet the regulatory purpose.

For pharmaceutical development, the last remaining driver foracute toxicity studies has been removed. There was consensus atthe workshop that information provided for first in man clinicaltrials was sufficient to assess overdose and that acute toxicity stud-ies provided no additional value. This information has fed into the

ICH M3 Question and Answer discussion process in 2010 and it iscritical that it is disseminated further. This review highlights theexciting prospect of providing Poison Centres and clinicians withthe key data needed to enhance their ability to treat patients whileminimising animal studies that are redundant in modern drugdevelopment.

5. Funding sources

This workshop was funded by the NC3Rs.

Conflict of interest

Dr. Wilks is a shareholder of AstraZeneca and Syngenta. Allother authors declare no conflict of interest.

Acknowledgments

The authors thank Vicky Robinson (NC3Rs) for chairing theacute toxicity workshop and for her helpful comments on thismanuscript. The authors are also grateful to the experts who par-ticipated in the NC3Rs workshop, who were from the organisationslisted below2:

David Coleman, Huntingdon Life Sciences; Kim Dalhoff, DanishPoison Information Centre; Elizabeth Donald, Charles River Labora-tories; Philippa Edwards, UK Health Protection Agency; RichardGreen, Syngenta; Robert Guest, Harlan Laboratories; Maren Her-manns-Clausen, Poison Information Center VIZ-Freiburg; AbbyJacobs, US Food and Drug Administration; David Jones, UK Medi-cines and Healthcare products Regulatory Agency; Tony Nash,AstraZeneca; Wendy Roosen, Johnson and Johnson; Elspeth Scott,Animal Science Procedures Inspectorate; Eugene Stankova, Bulgar-ian Poison Information Centre; Ruben Thanacoody, UK NationalPoisons Information Service (Newcastle); John Thompson, UKNational Poisons Information Service (Cardiff); Athina Tsamadou,Greek Poison Information Center; Ken Twomey, AstraZeneca; GeertVerstegen, Belgian National Poison Centre.

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