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Health Effects of Exposure to Active Pharmaceutical Ingredients (APIs)

Health Effects of Exposure to Active Pharmaceutical Ingredients (APIs)

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Health Effects of Exposure to Active Pharmaceutical Ingredients (APIs)
Health Effects of Exposure to Active Pharmaceutical Ingredients (APIs)

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IN-DEPTH REVIEW
Health effects of exposure to activepharmaceutical ingredients (APIs)
R. J. L. Heron
1
and F. C. Pickering
2
Background
Workers involved in the manufacture of pharmaceutical products are exposed in thecourse of their work to the active pharmaceutical ingredient (API) in the products.Such APIsare designed to produce biological change inthe humanbody,whichisanunacceptable outcome in the pharmaceutical worker.
Aim
To review the evidence for the presence of the health effects of APIs in thepharmaceutical industry.
Method
The study employed a literature review based on a systematic search of theMEDLINE database.
Results
Studies have shown that such biological effects can be produced, particularly inpersonnel working with potent compounds such as steroids, compounds withcapacity to cause cumulative damage such as cytotoxic anti-cancer drugs andantibiotics, unless careful risk assessment and appropriate control measures areimplemented.
Conclusion
There is limited epidemiological evidence for increased mortality and morbidityin this population, but adverse effects on health from exposure to potent agents,such as corticosteroids, sex hormones and antibiotics, can occur. The protection of workers from the potential harmful effects of APIs poses a significant challenge forthe pharmaceutical industry.
Key words
Active pharmaceutical ingredient; acute pharmacological effects; broncho-constriction; epidemiology; health effects; morbidity; mortality; occupationaldisease; respiratory sensitization; skin sensitization; steroids.
Received
15 May 2003
Revised
20 June 2003
Accepted
24 July 2003
Introduction
Workers involved in the manufacture of drug substancescan be exposed to active pharmaceutical ingredients(APIs) designed with the express intention of aninteraction with thehumansystem and modification ofitsfunctioning. Whilst such modification is generallydesirable in patients, any modification in function,whether positive or negative, is an unacceptable outcomein the pharmaceutical industry worker.In addition, developments in research for newcompounds and research techniques are creating newhazards. The process of delivering new medicines fromresearch idea to prescribed medicine takes much longerthan many expect and during the early part of thisdiscovery and development process there is the poten-tial for small teams of scientists to be exposed touncharacterized and untested therapeutic agents.Meanwhile, the technological basis of the industry israpidly changing. New methods of identifying biologic-ally active compounds by high-throughput screeningtechniques using cloned receptors are producingcompounds with ever-increasing potency, sometimes in
Occupational Medicine
,Vol. 53 No. 6© Society of Occupational Medicine; all rights reserved
357
1
Safety, Health & Risk Management,AstraZeneca,Alderley House,AlderleyPark,Cheshire SK10 4TF, UK.
2
Toxicologie Industrielle,Direction HSE, Sanofi-Synthelabo Groupe, 74–82Avenue Raspail,94255 Gentilly, France.Correspondence to:R. J. L. Heron, Safety, Health & Risk Management,AstraZeneca,Alderley House,Alderley Park,CheshireSK10 4TF,UK.Tel:+441625 512278; fax: +44 1625 586912; e-mail:richard.heron@astrazeneca.com
Occupational Medicine
2003;
53:
357–362DOI:10.1093/occmed/kqg115
 
the microgram range. In addition, new ranges of therapeutic agent are being developed based on a rapidlyincreasing understanding ofthe functioning ofthe humancell and the relationship between the activity of genesand the functions of the proteins they manufacture(genomics and proteomics). Using these techniques,biological compounds such as antigens can be producedwhich modify cell function in a fundamentally differentway to traditional chemical therapeutic agents. Ourknowledgeofthehazardslinkedtothesetechniquesisstillin its infancy and understanding ofthese hazards is one of the major challenges for the future.As the drug development cycle progresses, pharma-ceutical agents are subject to comprehensive regulatorytesting, both for efficacy and safety, and detailed pre-clinical and clinical toxicology information is generated,upon which worker occupational exposure limits can bebased.However,despite comprehensive risk managementsystems, studies have shown that worker health effectshave been experienced in the industry, particularly inpersonnel working with potent compounds such assteroids, or compounds with the capacity to causecumulative damage, such as cytotoxic anti-cancer drugs.
Method
To carry out this review, a systematic search of theMEDLINE database was undertaken (1966–November2002) using subject heading and key word searchesfor ‘pharmaceutical industry’ and ‘pharmaceuticalmanufacture’, together with terms for ‘occupationalexposure’,‘worker health’,‘overexposureand ‘hazardoussubstance’. All of the abstracts were reviewed and majorarticles retrieved and examined. In addition, bibliog-raphies of existing reviews were studied and furtherreferences followed up. In particular, the reviews byTeichmann
et al 
. [1] and Huyart [2] were of value in thisrespect.
Acute pharmacological effects
Most harmful effects resulting from exposure to pharma-ceutical agents are the result of acute pharmacologicaleffects, although reports in the literature are relativelyrare. It is possible that this reflects conservativeoccupational exposure limit setting practices, togetherwith short-term exposure patterns and effective exposurecontrols. It is also possible that many mild cases are onlyreported internally and are not published. Among thosewhich have been published is the case presented byAlbert
et al 
. [3], in which an operator working on themanufacture of glibenclamide was admitted to hospital inhypoglycaemic coma and the report of a study by Baxter
et al 
.[4],in which operators were found to have absorbedsignificant levels of barbiturates.
Chronic effects from potent compounds
The problems of highly potent compounds arehighlighted by the case presented by Jibani and Hodges[5], in which an operator suffered severe effects from theexcessive absorption of vitamin D3. This case is unusual,however, as the most common problems reported in theliterature have been linked to exposure to two specifictypes of potent compound: steroid hormones and cyto-toxic anti-cancer drugs.
Steroid hormones
Oestrogens and progestagens
The first report of adverse effects in workers related tooestrogens dates back to 1942,when Scarff and Smith [6]noted the development of gynaecomastia and loss of libido in men working with diethylstilboestrol.A series of reports throughout the 1970s and 1980shighlighted the problems of steroids, including those of Suciu
et al.
[7], showing an increase in psychologicaleffects, testicular discomfort and loss of libido in workersmanufacturing acetoprogesterone.An important studywasconductedbyHarrington
et al.
[8] looking at workers exposed to synthetic oestrogens.Of the 25 men studied, five were found to have effectslinked to steroid exposure, including gynaecomastia, lossof libido and galactorrhoea. Of the 30 women, 12 werefound to have menstrual breakthrough bleeding, a ratefour times more frequent than that in the controlpopulation. This study is interesting, as an attemptwas made to link clinical effects to exposure levels andbiological markers such as the plasma drug levels. Theinterpretation of the plasma drug levels proved difficult,as the relationship to exposure was not clear. To under-stand the true level of exposure, a series of samples isrequired over a defined period of time to determine thearea under the exposure versus plasma concentrationcurve.Itwas,however,notedthatthelevelswerehigherinthe workers with the higher exposure.Further studies by Shmunes and David [9]investigating workers exposed to diethylstilboestrol andMills
et al.
[10] confirmed the prevalence of problems atvery low levels of exposure.Taskinen
et al.
[11] conducted a register-based,case-control study on the pregnancy outcome of femaleworkers in eight Finnish pharmaceutical factories todetermine whether they had a higher risk of spontaneousabortion than the general population or matchedcontrols. In a logistic regression model (which includedoestrogen exposure, solvent exposure frequency of usageand heavy lifting), the odds ratio (OR) was increased foroestrogens (OR= 4.2,
= 0.05),aswellasfor continuousheavy lifting (OR = 5.7,
= 0.02).However,it is difficult
358
OCCUPATIONAL MEDICINE
 
to identify the contribution of the different exposurecomponents to this finding.In a more recent study, Shamy
et al.
[12] investigatedworkers exposed to ethinyloestradiol, levonorgestrol andprogesterone in the manufacture of oral contraceptives.The study looked at 18 men and 34 women. The womenwere principally performing blister packaging tasks andwere selected as being post-menopausal for at least2 years. The study found that oestrogen levels weresignificantly increased in both sexes and there was adecrease in testosterone in the male workers. There wasno difference in progesterone or gonadotrophins betweenthe exposed and control groups. The authors concludedthat liver dysfunction might have been responsible for thechanges in levels.
Corticosteroids
Newton
et al.
[13] found a diminution in corticotrophinsand grossly abnormal synacthen test results in two out of 12 workers involved in the manufacture of betametha-sone (no exposure data were provided). A 1987 casereport by Pezzarossa
et al.
[14] describes a pharma-ceutical worker involved in micronization of steroids,whowas also found to have symptomatic and biochemicaladrenal suppression. Total dust measurements in thework area showed values of 3.1 and 12.8mg/m
3
(theproportion of corticosteroid in the dust being 80% w/w).Six months after removal from exposure, hormonal andmetabolic features of adrenal suppression had largelysubsided. In 1988, Moroni
et al.
[15] studied a factory inwhich corticosteroids were manufactured.Adverse effectsfound included local effects on the skin such as acne anderythema and systemic effects, including hypertensionand effects suggestive of Cushing’s syndrome. The skinmanifestations improved during vacation periods andworsened during more intense work periods. However,they were unable to demonstrate a clear relationshipbetween the clinical manifestations and the levels of urinary 17-OH corticosteroids or plasma cortisol. It islikely that these levels changed very rapidly in response tothe level of corticosteroid absorbed, making themdifficult to use as a reliable biological marker.The evidence suggests that occupational steroid-related skin conditions may be induced by both systemicor local exposure and that in most cases the effects arereversible on cessation of exposure.
Cytotoxic anti-cancer drugs
The theoretical health risk from exposure to these drugsis very high. Although the therapeutic dose may byrelatively high, the therapeutic index is usually low. Also,unlike other drugs, therapeutic use involves pushingdoses to the limits of toxicity. These drugs can exertbiological effects even at very low levels of absorption.Also, as dosages are high, the quantities handled byworkers—and therefore the level of potential exposure— can be significant,which is unlike the situation with otherpotent compounds.The main studies in the pharmaceutical industry havebeen by Sessink
et al.
[16],who in 1993 studied exposureto methotrexate in a secondary manufacturing site.Atmospheric levels as high as 182 ug/m
3
were found inthe area in which the powders were dispensed. Urinaryexcretion of methotrexate was used as a method of determining absorption and an average level of 13.4
µ
g ina 24 h period was found. The workers in the area wore ahigh level of respiratory protection and the authorsconcluded that skin absorption was a major factor. In1994, Sessink [17] studied exposure to 5-fluorouracilby the measurement of a metabolite. Again, significantexposure in the dispensing area was found and significantcontamination of the work surfaces within the work areawas detected, which would provide opportunity for skinuptake.
Respiratory sensitization and bronchoconstriction
The development of adverse pharmacological effects isnot the only problem associated with exposure topharmaceuticals. Respiratory sensitization has beennoted in relation to exposure to several compounds. Twogroups of compounds have been particularly implicated:penicillin and cephalosporin antibiotics [18,19] andenzymes [20–23].Other chemical therapeutic agents noted to cause suchproblems include cimetidine [24], lisinopril [25],
α
-methyldopa [26] and salbutamol [27]. It is not alwaysclear in these cases whether the effect was sensitization orsecondary to a direct pharmacological effect caused by anaction of the inhaled dust on the respiratory tract. Aparticular problem is posed by the association of bronchoconstriction with exposure to opiates. This hasbeen reported by Agius [28], Biagini
et al.
[29] andGorski and Ulinski [30]. Biagini
et al.
[31] were ableto demonstrate the presence of antibodies to opiates.However, opiates are also known to have a histaminereleasing effect and it is possible that this forms the basisfor their broncho- constrictive properties.
Skin sensitization
Contact reactions resulting from skin exposure have beenreported in connection with pharmaceutical manu-facture. The underlying causes and steps for workerprotection are unchanged from those regarding anypotential skin sensitizer or irritant.Skin sensitization has been noted in relation to theexposure to several compounds. Examples include
R. J. L. HERON AND F. C. PICKERING: EXPOSURE TO ACTIVE PHARMACEUTICAL INGREDIENTS AND HEALTH
359

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