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# Current Intelligence Bulletin XX

Reproductive Risks Associated with Haza rdous Drug Exposure s in Healthcare

Workers and Recommendation s for Reducing Exposures

by

Thomas H. Connor, PhD

Christina C. Lawson, PhD

Martha Polovich, PhD, RN, AOCN

Melissa A. McDiar mid, MD, MPH, DABT



# DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Co ntrol and Prevention

National Institute for Occupa tional Safety and Health

Disclaimer: The findings and conc lusions in this report are those of the author and do not necessarily

represent the views of the National In stitute for Occupational Safety and Health (N IOSH). Mention of any

company or product does not constitute endorsemen t by NIOSH. In addition, citations to Web sites external to

NIOSH do not constitute NIOS H endorsement of th e sponsoring organi zations or their pr ograms or products.

Furthermore, NIOSH is not responsible for the content of these Web sites. All Web addresses referenced in

this document were accessible as of the publication date.

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This document is in the public domain a nd may be freely copied or reprinted.



# Disclaimer

Ordering Information

To receive documents or other information about o ccupational safety and heal th topics, contact NIOSH

at

DHHS (NIOSH) Publication No. 2012–XXX

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# Foreword

T he purpose of this Current Intelligence Bulleti n is to increase awareness among healthcare

workers and their employers about the potential adverse reproductive he alth effects from working with

antineoplastic and other hazardous drugs. In addition, it will provide measures for protecting the reproductive health of workers and the he alth of their offspring. Healthcar e workers who prepare or administer hazardous drugs or who work in areas where these drugs are used can be exposed when these agents

are in the air or on work surfaces, drug vials and c ontainers, contaminated clothing, medical equipment,

and patient excreta. Workplace exposures to hazardous drugs have been associated with health effects

such as skin disorders, adverse reproductive outcomes (including infertility, mi scarriage, and congenital

malformations), and possibly leukemia and other cancers . Of these, reproductive health is one of the

most vulnerable endpoints, because many hazardous drugs used for cancer treatment target rapidly dividing cells in the same way terato gens target rapidly dividing embr yonic cells. The risk can be influenced by the timing of the exposure and the pot ency and toxicity of the hazardous drug.

The production, distribution, clinical preparation, administration, a nd disposal of pharmaceutical

products are widespread and essential to the h ealthcare industry. New areas of pharmaceutical development are continually br inging new drugs and fundamental cha nges to methods for treating and preventing or minimizing diseases. At the same time, a large number of medications or mixed exposures

can be hazardous to healthcare workers who handle them and to their fetuses or nursing offspring. This

NIOSH Current Intelligence Bulletin will help make workers and employers more aware of these hazards and provide recommendations for preventing exposures.

This Current Intelligence Bulletin applies to all hea lthcare workers who might handle hazardous

drugs, such as pharmacists and pharmacy technicians, registered nurses, advanced practice registered

nurses, licensed practical/vo cational nurses, nurses’ aides, physicia ns, physicians’ assistants, operating

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room personnel, shipping and receiving personnel , waste handlers, maintenance workers, laundry

workers, laboratory personnel, and workers in vete rinary practices. The current number of healthcare

workers in the United States potentially exposed to hazardous drugs exceeds 8 million. However, not

all of these workers will be expos ed to hazardous drugs, and only a fraction of those who are exposed

will be at reproductive risk. Workers in the drug manu facturing sector may also be exposed to hazardous drugs. However, the primary focus of this Current Intelligence Bulletin is workers in healthcare

settings because of their unique potential to be in an environment of multiple exposures.

John Howard, MD

Director

N ational Institute for Occupational

Safety and Health

Centers for Disease Control and

Prevention

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# Abstract

Healthcare workers who handle, compound (prepare ), administer, or dispose of hazardous drugs

can incur risks to their health, including re productive harm. This document describes the

vulnerability of workers, fetuses, and nursing infants of exposed workers to reproductive and

health hazards and reviews human and animal studies of exposure to hazardous drugs. On the basis of a review of published data, the National Institute for Occupational Safety and Health

(NIOSH) recommends steps to reduce employee e xposure to hazardous drugs for all healthcare

workers and especially those at reproductive risk. Special consider ation may be needed for those

workers with underlying medical conditions that ma y put a worker at exceptional risk of harm.

These steps involve adhering to established indust rial hygiene procedures, education and training

for employees and employers on the safe handling of hazardous drugs, and including the

implementation of an alternative duty program when exposure cannot be eliminated. Employers

and all workers in health care settings (including employees and nonemployees such as contractors

and credentialed providers) can work together to establish a program to provide a safe working

environment for all healthcare workers, especially those who are at reproductive risk if exposed to

hazardous drugs.

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# Contents

Foreword

Abstract

Acknowledgments

Abbreviations

Glossary

Reproductive Risks Associated with Hazardous Drug Exposures in Healthcare Workers and

Recommendations for Reducing Exposures

Background

Description of Exposure

When is a Worker Particularly Vu lnerable to Reproductive Hazards?

Vulnerability of the Developing Fetus and Newborns

Experimental Studies

Animal Studies

Human Studies

Patients Treated with Antineoplastic Drugs

Patients Treated with Drugs Other Than Antineoplastic Drugs

Healthcare Workers Exposed to Hazardous Drugs

Exposure to Antineoplastic Drugs

Recommendations

Use of Industrial Hygiene Practices to Reduce Exposure to Hazardous Drugs

Implementation of an Alternative Duty or Temporary Reassignment Program

Medical, Legal and Ethical Implications

Summary

References

Tables

Table 1. Review of Reproductive Epidemio logy Studies of Occupational Exposure to

Antineoplastic Drugs

Figures

Figure 1. Initial Healthand Safety Assessment for Couples Trying to Conceive and Women who

are Pregnant or Breast Feeding

Appendices

Appendix 1. Hazardous Drug Handling Activities in Healthcare Settings that can Result in

Exposure

Appendix 2. FDA Pregnancy Categories of Dr ugs that should be Handled as Hazardous

Appendix 3. FDA-Assigned Pregnancy Categories

Appendix 4. Databases Reviewed

Appendix 5. Reproductive Health Recommenda tions for Alternativ e Duty Practices



# Acknowledgments

The authors thank the following individuals for their assistance in reviewing this document: Kathleen

Connick

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Editorial review and production assistance were provided by Susan Afanuh a nd Vanessa B. Williams.

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# Abbreviations

AHFS

ANA American Hospital Formulary Service

American Nurses Association

ASHP American Society of Health System-Pharmacists

(Formerly known as American Society of Hospital

Pharmacy)

BSC Biological safety cabinet

CACI

CAPhO

CFR Compounding aseptic containment isolator

Canadian Association of Pharmacy in Oncology

Code of Federal Regulations

CSTD

HSE

IARC Closed system drug-transfer device

Health and Safety Executive

International Agency for Research on Cancer

NIOSH

NRC

NTP National Institute for Occupational Safety and

Health

Nuclear Regulatory Commission

National Toxicology Program

OSHA Occupational Safety a nd Health Administration

ONS Oncology Nursing Society

PPE

SDS Personal protective equipment

Safety Data Sheet (Formally Material Safety Data

Sheet)

USP United States Pharmacopeial Convention

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# Glossary

Alternative duty: Temporary reassi gnment of duties, often within th e same job, to avoid hazardous situations or agents (in this case, exposure to hazardous drugs).

Antineoplastic drug: A chemotherapeu tic agent that controls or kills cancer cells. Drugs used in the

treatment of cancer are cyto toxic but are generally more damaging to dividing cells than to resting cells.

Carcinogenicity: The ability or tendency to produce cancer.

Chemotherapy drug: A chemical agent used to treat diseases. The term usually refers to a drug used to

treat cancer. Similar drugs are also k nown as antineoplastic and cytotoxic.

Closed system drug-transfer devices (CDTDs): A drug transfer device that mechanically prohibits the

transfer of environmental contamin ants into the system and the es cape of hazardous drug or vapor concentrations outside the system.

Cytotoxic: A pharmacologic compound that is detrimental or destru ctive to cells within the body.

Engineering controls: Devices desi gned to eliminate or reduce workerexposures to chemical, biological, radiological, ergonomic, or physi cal hazards. Examples of those used in healthcare include laboratory fume hoods, glove bags, needleless systems, closedsystem transfer devices, biological safety cabinets, containment isolators, and robotic systems.

Genotoxicity: The ability to damage or mutate DNA. Genotoxic substances ar e not necessarily carcinogenic.

Hazardous drug: Any drug identified by at least one of the following criteria: carcinogenicity; teratogenicity or developmental toxicity ; reproductive toxicity in humans; or gan toxicity at low doses in humans or animals; genotoxicity; or new drugs that mimi c existing hazardous drugs in structure or toxicity.

Healthcare workers: All workers w ho are involved directly or indirectly in the care of patients. Examples of those at risk for exposur e to hazardous drugs include pharmaci sts; pharmacy technicians; registered nurses, advanced practice registered nurses; licensed practical/vocational nurses; nurses’ aides;

physicians; physicians’ assistants; home healthcare workers; and workers in environmental services

(housekeeping, laundry, a nd waste disposal).

Mutagenicity: The ability of increasing the sponta neous mutation rate by cau sing changes in the DNA.

Personal protective equipment (PPE): Items such as gloves, gowns, respirators, goggles, face shields,

and others that protect indivi dual workers from hazardous physical or chemical exposures.

Reproductive hazard: An agent that in terferes with the ability of a coupl e to achieve a su ccessful birth.

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Reproductive hazards affect fertility, conception, pregnancy, and/or delivery.

Reproductive risk: Reproductive risk refers to risks to the reproductive systems of adult men and women, and outcomes of pregnancies, including: measur ements of fertility in men and women, menstrual

function, miscarriage (spontaneous abortion), preterm birth, abnormal birth weight, and developmental

and reproductive outcomes in offspring.

Reproductive toxicity: The ability to cause adverse effects on the male and/or female reproductive system.

Risk assessment: Characterization of potentially adverse health effects from human exposure to environmental or occupational hazards. Risk assessment can be divided into five major steps: hazard identification, dose–response assessment, exposure assessment, risk characterization, a nd risk communication.

Susceptible populations: Those indivi duals with medical history or pe rsonal fertility history (e.g., repeated miscarriages) or any other underlying medical c onditions that may put them at exceptional risk of

harm.

Temporary reassignment: An assignment to another posi tion, at the same pay scale, for a specified period. At the end of the temporary rea ssignment, the employee returns to the original position or to a position of comparable status, tenure, and pay.

Teratogenicity: The capability of producing fetal malformations.

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# Reproductive	Risks	Associated	with	Hazardous	Drug	Exposures	in

Healthcare	Workers	and	Recommendations	to	Reduce	Exposures

Background

The acute and chronic toxicity of antineoplastic dr ugs is well recognized in treated patients including

their reproductive and developmental toxicity. H ealthcare workers who compound (prepare) or administer antineoplastic drugs, or who work in areas where these drugs are used can be exposed to these agents

when they are present on contaminated work surfaces , drug vials and containers, contaminated clothing

and medical equipment, and in patient excreta and s ecretions such as urine, feces, vomitus, and sweat

(Appendix 1). The National Institute for Occupationa l Safety and Health (NIOSH) has developed an

approach to minimizing exposure to antineoplastic a nd other hazardous drugs with the publication of the

NIOSH Alert: Preventing Occupati onal Exposures to Antineoplasti c and Other Hazardous Drugs in

Health Care Settings [NIOSH 2004] that includes a combination of industrial hygiene practices, starting

with engineering controls. Engineering controls pl ace a barrier between the worker and the hazard to

reduce exposure. These engineering controls include biological safety cabinets (BSCs) or compounding

aseptic containment isolators (CACIs), closed system transfer devices (CSTDs), robotic systems, and

needleless systems. Additional controls should include vigilant adherence to safe work practices and

administrative controls. The use of personal protect ive equipment (such as gowns, gloves, and eye and

respiratory protection) is also essent ial for worker prot ection [NIOSH 2009].

Measurement of surface contamination is currently th e best indication of the level of environmental

contamination in areas where haza rdous drugs are prepared, administ ered to patients, or otherwise

handled (such as receiving areas, transit routes throughout the facilit y, and waste storage areas) [Hon et

al. 2011]. In a follow-up study, Hon and coworkers [ 2014] reported that 20% of the workers sampled

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had detectable amounts of cyclophospha mide on their hands. Studies that have attempted to do so have

shown an association between surf ace contamination and worker expos ure [Pethran et al. 2003; Connor

et al. 2010; Villarini 2011], and surf ace contamination is the most comm only used metric for evaluating

the workplace for hazardous drugs. Workplace contamin ation with hazardous drugs in the United States

has not changed considerably over the past decade or more [Connor et al. 1999; 2010, Wick et al. 2003;

Sessink et al 2011; 2013]. This finding indicates that worker exposure probably has remained constant

over that time, despite efforts to reduce or eliminate environmental contamination.

The introduction of Class II BSCs for the preparat ion of hazardous drugs in the 1980s substantially

reduced the potential for worker ex posure [Anderson et al. 1982], but no t as efficiently as first believed

[Connor et al. 1999]. The more recent use of CACIs ha s not been widespread, and these have not been

proven to offer more protection to wo rkers than BSCs [Seger et al. 2012 ]. The use of robotic systems to

prepare hazardous drugs may reduce environmental co ntamination and worker exposure to these drugs.

However, their high cost makes them prohibitive for mo st facilities [Seger et al. 2012]. The addition of

CSTDs for the preparation and administration of hazardous drugs has been shown to reduce surface

contamination and possibly worker exposure, but they do not totally eliminat e them [Connor et al. 2002;

Wick et al. 2003; Harrison et al. 2006; Sessink et al. 2011, 2013]. Desp ite improvements in engineering

controls and other attempts to reduce environmental contamination, hazardous drugs are still being

released into the work environment and workers are being exposed to them. Therefore, for the

foreseeable future, contamination of the workplace with hazardous drugs and/or worker exposure to

them will be an issue with no suitable solution.

Recent research has shown that even when all of th ese controls are used in healthcare settings, the

potential for exposure to antineoplastic drugs cannot be completely eliminated [Schierl et al. 2009;

Connor et al. 2010; Siderov et al. 20 10; Yoshida et al. 2010; Davis et al. 2011; Sessink et al. 2011; Turci

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et al. 2011; Chu et al. 2012; Polovich and Martin 2011; K opp et al. 2013]. Therefore, an additional level

of protection might be required for those healthcare workers w ho are most vulnerable to the

reproductive and developmental effects of hazard ous drugs in the form of voluntary temporary

alternative duty.[ASHP 1990, 2006; OSHA 1999; HSE 2003; Lawson et al. 2006; ACOEM 2011; ONS

2009; 2011].



# Description of Exposure

In 2004, NIOSH published an alert on antineoplastic and other hazardous drugs that describes safe

handling practices for all healthcare workers [NIOSH 2004]. The alert included a li st of drugs that were

considered hazardous to workers. That list of hazardous drugs was most recently updated in 2014 to

include drugs newly approved by the U.S. Food a nd Drug Administration (FDA) and other drugs with

new FDA safety warnings based on post-marketi ng information [NIOSH 2014 ]. This document also

contains new guidance on the safe handling of hazardous drugs. Approximately half of the drugs listed

as hazardous by NIOSH are classified as antineopl astic, and the remainder comprise hormonal agents,

immunosuppressants, antiviral agents, and others. A lthough the current document pertains to published

information on exposure to primarily antineoplastic drugs, the information and recommendations herein

can be generalized to include other hazardous drugs.

Appendix 2 lists all drugs that NIOSH considers poten tially hazardous to healthcare workers as of 2014

[NIOSH 2014]. Of the 184 drugs list ed, 99 are FDA Pregnancy Categor y D and 43 are Pregnancy Category X; the remainder of the listed drugs is Category C or B. For Category D drugs, there is positive evidence of human fetal risk, based on adverse reaction data from investig ational or marketing experience

or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks to the fetus (Appendix 3). Category X drugs are those for which the fetal risk clearly outweighs the benefits to patients [Tim pe et al. 2004; Briggs et al. 2008; 21 CFR 201.5 7(c)(9)(i)]. Most of

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the remaining 30 percent of the drugs are classified as Category C, in which animal reproduction studies

have shown an adverse effect on the fetus; there ha ve been no adequate, well-controlled studies in humans, but the potential benefits might warrant use of a Category C drug in pregnant patients despite the

fetal risks. However, many drugs classified as Cate gory C have reproductive warnings or properties similar to those of the drugs in Catego ry D. Four of the drugs are classi fied as Category B, which differs

from Category C in that animal repro duction studies have failed to demons trate a risk to the fetus, but is

similar in that there have not been adequate stud ies in humans and there is still potential for concern

(Appendix 2). According to the FDA, the curren t pregnancy category labeling may be misleading [FDA,

2008]. Using A, B, C, D and X to describe the risk of fetal harm implies that risk increases from one

category to the next. In fact, C- a nd D-category drugs may have risks sim ilar to those in category X, but

risk is weighed against benefit. When considered in the context of occupational exposure, there are no

benefits associated with drug expos ure; therefore, occupational expos ure of pregnant workers cannot be

assumed to be harmless especially since the workers may be exposed to multiple hazardous drugs daily

over many years. Because exposure to drugs that have adverse reproductive effects is possible in many

healthcare settings, additional precau tions and safeguards might be required to better protect vulnerable

populations such as fetuse s and breastfed infants.

By definition, a reproductive hazard affects the reproduc tive function of women or men or the ability of

couples to conceive or bear h ealthy children [HSE 2003]. Some ch emicals, including many hazardous

drugs, are considered reproductive hazards on th e basis of laboratory studies in animals or

epidemiological studies in humans that show they can affect fertility or pr egnancy outcomes or cause

birth defects. A substantial number of these drugs ha ve been identified by NIOSH as hazardous and are

also known or suspected human car cinogens [IARC 2014]. Many are tera togenic and/or have adverse

reproductive effects. In addition, numerous highly h azardous but therapeutically useful drugs are known

to be present in the breast milk of women who ar e being treated with them [Briggs et al. 2008]. Most

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hazardous drugs are used to treat illnesses such as cancer, autoimmune disorders, or human immunodeficiency virus infection [NIOSH 2004; 2014]. Howe ver, healthcare worker s who are unintentionally

exposed to these drugs at work face several health risks, including reproductive risks (e.g., risks to the

reproductive systems of adult men and women, and outcomes of pregnancies).

In the United States, an estimated 8 million healthcare workers [BLS 2011] are potentially exposed to

hazardous drugs at their worksites. It is not know n how many are exposed to hazardous drugs but many

of these workers are women of reproductive age a nd should be aware of th e potential [Hood 2008; Alex

2011]. Because the estimated number of U.S. worker s potentially exposed to h azardous drugs is based

on job classifications and work locations, not all of th e workers in a particular job classification will be

exposed. In addition, for males, th e only reproductive risk is exposur e during the peri od leading up to

conception. Women who are not at risk for adverse reproductive outcomes are those who cannot

conceive, are utilizing reliable m eans of contraception, or are post- menopausal. Therefore, the actual

number of men and women who ma y be at reproductive risk whil e exposed to hazardous drugs is

considerably less than 8 million. Howe ver, because of the nature of th ese drugs, workers may be at risk

for other adverse health outcomes, such as acute and chronic effect s of drug exposure.

These workers include pharmacists and pharmacy techni cians, registered nurses, advanced practice registered nurses, licensed practical/vocational nurses, nur ses’ aides, physicians, physicians’ assistants,

operating room personnel, shipping and receiving pe rsonnel, waste handlers, maintenance workers,

laundry workers, laboratory personnel, and workers in veterinary practices and potentially others working in healthcare settings who come into contact with drugs or drug waste [NIOSH 2004]. Healthcare

workers are exposed to hazardous drugs when th ey compound, administer, or dispose of hazardous

drugs, clean up spills or patient waste, or touch surf aces that are contaminated with these drugs. These

activities can create aerosols or generate dust, thereby in creasing exposure [O SHA 1999; NIOSH 2004;

ASHP 2006; ONS 2011]. Skin absorption and inhalation are the most common ways a healthcare worker

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may be exposed to hazardous drugs. However, i ngestion (from hand-to-mout h contact), accidental

injection through a needle stick, or other shar ps injury is also possible [NIOSH 2014].



# When	is	a	Worker	Particularly	Vulnerable	to	Reproductive	Hazard s?

Antineoplastic drugs can affect re productive function in both males a nd females exposed to the drug.

For reproductive health hazards, there is a “window of risk” when men and women are particularly

vulnerable. In women treated with antineoplastic drugs, adverse eff ects have been reported including

damage to ovarian follicles, decreased ovarian volume , and ovarian fibrosis resulting in amenorrhea and

menopausal and other symptoms [Knobf 2006]. For pregnant women, the wind ow of risk begins

approximately one month before conception and last s through the pregnancy. Ho wever, specific drugs

may remain in the body for an extended period of ti me, especially if exposure is continuous. In

addition, some drugs are known to enter the breast milk of treated patients [NIOSH 1996, 1999; HSE

2003; Briggs et al. 2008]; therefore, the infants of healthcare workers could be exposed during

breastfeeding.

In men, reported adverse effects include primary or secondary hormonal changes. In addition, a man can

expose his female partner and/or her developing fetu s via contaminants on his skin or clothing, or during

sexual intercourse [Pichini et al. 1994]. Men produce sperm over approximately a 2-month cycle;

therefore, a man’s sperm is vulne rable to hazardous exposures from as early as 2 months before

conception [Maltaris et al. 2006]. Consequently, both male and female workers who are handling

hazardous drugs during any of these critical reproductiv e periods should be especially aware of risks to

the health of their offspring.



# Vulnerability	of	the	Developing	Fetus	and	Newborns

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Although adults can be adversely a ffected by prolonged exposures to cer tain chemicals, developing fetuses and newborns up to the age of 6 months are usua lly more sensitive to chem ical toxicity because of

the incomplete development of systems for biotrans formation/detoxification and elimination of toxicants. Unlike older children and adul ts, such pathways are underdevel oped and cannot efficiently detoxify or excrete drugs. Therefore, toxicants remain in higher concentrations in the blood for longer periods

[Scheuplein et al. 2002]. Examples of toxic substances and carcinogens that affect infants more than

adults include some pesticides, tobacco smoke, radi ation, and a variety of ch emicals. With many chemical exposures, it is known that the fetus is more sus ceptible than the mother to the toxic chemical [NRC

1993; Goldman 1995; Scheuplein et al. 2002; Brent et al. 2004; Perera 2011]. In addition, studies have

shown that exposure to chemicals and radiation in ut ero and early in life can disproportionally increase

the occurrence of childhood cancer compared with exposures that occur later in life [Perera 2011].

Reproductive effects might occur at lower exposure concentrations th an exposure limits established by

the Occupational Safety and Hea lth Administration (OS HA) or recommended by NIOSH [2010] or the

American Conference of Government al Industrial Hygienists [ACGIH 2012]. This is because many of

these limits are based on protecting adult workers from health effects other than repro ductive endpoints

(for example, neurotoxicity or cancer). In 19 91, the General Accounting Office (GAO) reviewed

regulations on environmental chemicals known to cause adverse reproductive and developmental

outcomes. They reported that two-thirds of the majo r regulatory decisions for the 30 chemicals reviewed

were based on cancer and acute toxi city, not reproductive or developm ental effects [U.S. GAO 1991]. In

addition, in most cases, exposure lim its have not been established for hazardous drugs [NIOSH 2004].

Because the placenta is not an effective barrier to low-molecular-weight molecules, many of the

antineoplastic and other hazardous drugs can reach the fetus in concentrations that could have

deleterious effects [Arnon et al. 200 1]. Drugs with a molecular weight of less than 600 Daltons usually

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cross the placenta; t hose with molecular weights greater than 1000 Daltons typicall y do not. Since many

antineoplastic drugs have a molecular weight within these parameters, they can readily cross the

placenta [Pacifici and Nottoli 1995]. In addition, the placenta is also more permeable to lipophilic

chemicals and drugs. Moreover, it has been hypothesi zed that many antineoplastic drugs actually target

developing fetuses in the same way they target th e rapidly proliferating ce lls and active DNA metabolism of cancer cells [Selig et al. 2012].



# Experimental Studies

Animal	Studies

Laboratory studies have dem onstrated that many antineoplastic drugs are teratogenic, often in more than

one animal species. Some classes of drugs are mo re hazardous than others [Shepard 1995; Schardein

2000]. As a group, the antineoplastic drugs have been s hown in animal studies to be some of the most

potent teratogenic agents known at doses typically used in cancer treatment. Alkylating agents,

anthracycline antineoplastic antibiotics, and antimetabolites all have potent teratogenic activity in multiple animal species. Antimetabolites are associated with birth defects more frequently than other

antineoplastic agents. Alkylating agents are generall y less teratogenic than the antimetabolites. Vinca

alkaloids are potent teratogens in animals but do not appear to have similar effects in humans [Meirow

and Schiff 2005]. Many antineoplastic drugs, in addition to the alkylating agents and antimetabolites, are

also teratogenic in laboratory animals. In addi tion to the antineoplastic drugs, numerous other drugs

have been demonstrated to be teratogenic in one or more species [Schardein 2000]. Preclinical laboratory testing of drugs in general demonstrates variou s adverse effects on reproduction and fertility, often in

the absence of maternal toxicity [NIOSH 2004; 2014]. Additional info rmation on teratogenic, reproductive, and fertility effects of specific drugs can be found in the drug package inserts and in the Safety Data Sheets (SDSs).

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# Human	Studies

Patients Treated with Antineoplastic Drugs

Infertility following treatment with antineoplas tic drugs has been reported for both men and

women because of the gonadal toxicity of the drugs [McInnes and Schilsky 1996; Maltaris et al. 2007].

A number of individual antineoplasti c drugs and some combinations of antineoplastic drugs have been

identified as causing gonadal dysfu nction in male cancer patients [Mei strich et al. 1997; Wallace et al.

2005]. Individual drugs such as cyclophosphamide, melphalan, chlorambucil, procarbazine, and

cisplatin and drug combinations such as MOPP (nitrogen mustard, oncovin, procarbazine, and

prednisone) have produced prolonged azoospermia in males [Wallace et al. 2005]. The teratogenic

effects on the fetuses of women treated with thes e drugs are well documented [Shepard 1995; Schardein

2000; Meirow and Schiff 2005; Shahab and Doll 2008; Azim et al. 2010a,b; NTP 2013]. The observed

teratogenic effects depend on the drug, the dose, and th e developmental stage of the fetus at exposure.

Schardein [2000] lists several common antineoplasti c drugs as human teratogens. Although information

is available from human studies ab out individual drug exposures, mo st malignancies are treated with

multi-drug regimens [Azim et al. 2010a,b]. Therefor e, many of the known teratogenic effects of

individual drugs have been de rived from animal studies.

Three recent publications have reviewed the effect s of cancer treatment on th e developing fetus. The

first reported the effects of antineoplastic drugs used to treat solid tumors, primarily breast and ovarian

cancers [Azim et al. 2010a,b; Seli g et al. 2012]. Although data are lim ited or not available for many

drugs, the authors concluded that, in general, antineoplastic drugs have adverse effects on the fetus

during the first trimester. Exposure during the first 2

− 3 weeks of pregnancy typically results in

miscarriage, but not teratogenesis [Azim 2010a]. In patients treated with these drugs, brief exposures

during early pregnancy to antineoplas tic drugs (those for which there ar e data) had little effect on the

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fetus. However, continued exposure resulted in conge nital anomaly rate s of approximately 20% which is

in contrast to background rates that are normally 3-4 %. Most of the antineoplastic drugs they reviewed

had little effect on the fetus in th e second and third trimesters, with the exception of methotrexate. Since

methotrexate causes malformations, the authors concl uded this drug should be avoided altogether during

pregnancy.

The second article reviewed antineopl astic drugs used in the treatment of hematological tumors [Azim et

al. 2010b]. In contrast to the drugs used to treat solid tumors, those used to tr eat hematological tumors

were significantly associated with both miscarriages and fetal malformations when administered during

the first trimester. Pa tients treated with imatinib during the first trimester but not the second were at high

risk of fetal malformations. Daunorubi cin and idarubicin have been asso ciated with a high incidence of

fetal malformations even when administered after the first trimester, and therefore they should be

avoided throughout pregnancy.

The third review article [Selig et al. 2012] evaluated the adverse repr oductive effects of single-agent and

combination therapy and reported outcomes similar to those of Azim [2010 a,b]. They reported that the

antimetabolites and alkylating agents had the hi ghest rates of adverse pregnancy outcomes in

comparison with mitotic inhibitors and antibiotics. Findi ngs about single-agent exposures were mixed,

perhaps due to small sample sizes, but Selig et al . noted that exposure of the fetus during the first

trimester was most critical. A recent report by th e National Toxicology Program [NTP 2013] provides a

comprehensive summary of the effects of some antineoplastic drugs on reproductive outcomes in

patients. This report also briefly addresses occu pational exposure to these drugs and possible adverse

reproductive outcomes in healthcare workers. A larg e number of antineoplastic drugs are available for

treatment of cancer and other diseases, and data are not available for all drugs regarding adverse

reproductive effects. However, most of these drugs have an adverse effect

― especially resulting in

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miscarriages

― when given during the first trimeste r, particularly during the first 2

− 3 weeks of

pregnancy.

In summary, data from studies of patients being treated for cancer indicate that the first trimester is the

most vulnerable time for exposure to result in adverse effects such as miscarriage and birth defects. This

finding is supported by the recent study [Lawson et al. 2012] of occupational exposures among nursing

personnel, which showed a stronger a ssociation of exposure to antineopl astic drugs with first-trimester

miscarriages than with second-trimester miscarriag es. However, as mentioned above, some drugs such

as methotrexate, daunorubicin, and idarubicin might also have an e ffect on the fetus during the second

and third trimesters. Post-marketing reports of a dverse reproductive effects in patients and their

offspring can often be found in the drug package inserts and the SDSs.



# Patients Treated with Hazardous Drugs Other Than Antineoplastic Drugs

Although the occupational studies list ed in Table 1 dealt with antineopl astic drugs used to treat cancer,

NIOSH has identified hazardous drugs that are us ed to treat noncancerous conditions [NIOSH 2004;

2014]. Many of these drugs are repr oductive hazards and are classifi ed as FDA Pregnancy Category D

or X (Appendix 2). Some examples of adverse reproduc tive effects in patients treated with hazardous

drugs other than antineoplastic drugs include the following:

 Thalidomide, though now used as a cancer treatme nt, has caused severe birth defects or fetal

death following treatment of pregnant women fo r morning sickness. It is now available only

under a restricted distribution program in orde r to prevent fetal exposure [Shahab and Doll

2008].

 Diethylstilbestrol (DES), also co mmonly used in veterinary medici ne, has been associated with

# 22

an increased risk of breast can cer in women who took th is drug and is linked to breast, vaginal,

and cervical cancers in th e daughters of women who took it during their pre gnancies [Hatch et al.

1998; Palmer et al. 2002]. Adverse effects, including increased rates of testicular cancer in male

offspring of treated mothers, have also been reported [Strohsnitter and Noller 2001].

 The anti-seizure medication valproic acid and pr oducts containing valproic acid are associated

with increased risk of major malformations, in cluding neural tube def ects, when taken during

pregnancy. In addition, children of mothers who took one of these drugs during pregnancy have

an increased risk of low cognitive test scores [Garry and Truran 2011].

 When Paxil, an antidepressant, is taken during the first trimester, there is evidence of increased

risk of birth defects, particularly heart defects [GlaxoSmithKline 2011].

 Ribavirin, an antiviral drug administered via nebu lizer, can cause harm or death to the fetus in

women taking it when they become pregnant. Feta l harm or death may also occur if the father

was taking it when his partner became pregnant. Thus, for both men and women taking ribavirin,

there are warnings against pregnancy. Two forms of birth control are re quired for both men and

women, along with monthly pregnanc y tests for women taking ribavi rin and for female partners

of men during treatment. The pregnancy tests must continue for 6 months after treatment [Merck

Sharp & Dohme 2003].

 Finasteride, a drug used to treat benign prostati c hypertrophy, can be absorbed through the skin.

If the film coating of the tablet has been broken or the tablet crushed, it should not be handled by

a woman who is pregnant or may potentially be pr egnant due to the potential risk to the male

fetus [Merck Sharp & Dohme 2014].



# Healthcare	Workers	Exposed	to	Hazardous	Drugs

Exposure to Antineoplastic Drugs

# 23

An extensive review of the litera ture linking occupational exposure to antineoplastic drugs and adverse

reproductive effects was conducted through February 2014 using the databases as listed in Appendix 4.

Tables 1-3 include studies of hea lthcare workers occupationally exposed to antineoplastic drugs and the

occurrence of adverse reproductive outcomes, including infertility, miscarriages, stillbirths, pregnancy

outcomes, and congenital malformations. All relevant published studies from the open literature were

included in this summary. These data were summarized by Connor et al. [2014].

Table 1 summarizes 8 studies of occupational exposur e to antineoplastic drugs and congenital anomalies

observed in offspring of workers. Th e primary limitation of these studies is the small sample sizes; five

of the eight studies had 10 or fewe r exposed cases, and all studies had fewer than 20 exposed cases. The

small sample sizes resulted in several other important limitations. These included a limited ability to

adjust for confounding; the need to group anomalies th at had different etiologies; and wide confidence

intervals, which reflect poor statisti cal power. However, of the studies that had more than five exposed

cases, three showed significantly increased risks associated with exposure [Hemminki et al. 1985;

McDonald et al. 1988; Peelen et al. 1999], and two s howed increased risks that were not statistically

significant [Skov et al. 1992; Ratner et al. 2010]. The odds ratios of adjusted models ranged from 1.36

(95% confidence interval, 0.59–3.14) [Skov et al. 1992] to 5.1 (95% confidence interval, 1.1–23.6)

[Peelen et al. 1999]. A meta-analysis [Dranitsaris et al. 2005] of four studi es with exposure periods

ranging from 1966 to 1985 [Skov et al. 1992; Hemminki et al. 1985; Peel en et al. 1999; McAbee et al.

1993] reported a crude odds ratio of 1.64 (95% confidence interval, 0.91–2.94) for all congenital

anomalies combined. Although the preceeding studies suggest an increase d risk for congenital

anomalies with maternal occupational exposure, the limitations and wide confidence intervals make the

size of the adverse effect uncertai n. In addition, studies that reflect current exposure levels are needed,

because the studies published to date include data th at were collected before the year 2000, the majority

# 24

of which were conducted prior to 1985.

Studies of maternal occupational ex posure to antineoplastic drugs and miscarriage are shown in Table 2.

We identified eight studies of miscarriage, an add itional three studies that analyzed combined outcomes

of miscarriage and stillbirth, four st udies of stillbirths, and two studies of tubal pregnancies. The studies

of miscarriage had mixed results, and three of these studies were limited by small sample sizes (fewer

than 20 exposed cases). The three largest studies [Stü cker et al. 1990; Valanis et al. 1999; Lawson et al.

2012] showed increased occurrence of miscarriages among women who reported handling antineoplastic

drugs during the first trimester. Most exposures were among oncology nurses or pharmacists. Other

studies that did not find statistical ly significant associations had odds ratios ranging from 0.7 to 2.8. A

meta-analysis that pooled the results of five studies [Selevan et al. 1985; Stücker et al. 1990; Valanis et

al. 1999; Skov et al. 1992; Peelen et al. 1999] found an overall adjusted increased risk of 46% among

exposed workers (95% confidence interval, 11% to 92 %) [Dranitsaris et al. 2005]. All studies published

to date contain data collected before 2002.

More research is needed to examine the effects of occupational exposure to antineoplastic drugs and

stillbirth because this is an uncommon outcome and therefore difficult to study. All of the studies of

stillbirths (or of fetal loss, which combines miscar riage and stillbirth) had insufficient numbers of

exposed cases (n = 1 to 13), resu lting in wide confidence interval s [McDonald 1988; McAbee et al.

1993; Rogers and Emmet 1987; Dranitsar is et al. 2005; Fransman et al. 2007; Peelen et al. 1999; Valanis

et al. 1999; Ratner et al. 2010]. We found only two studies of tubal preg nancies, both with 10 or fewer

exposed cases, and the results varied widely from OR=0.95 (95% CI 0.39-2.31) [Bouyer et al. 1998] to

OR 11.4 (95% CI 2.7-17.6) [Saurel-Cubizolles et al. 1993].

# 25

We found only two studies of occ upational exposure to antineoplastic drugs and fertility or time to

pregnancy (Table 3), though the results suggest that exposure to antineoplastic drugs is associated with

an increased risk of subfertility [Valanis et al . 1997; Fransman et al. 2007] . Only one study evaluated

menstrual cycle; it showed a statistically signifi cant three-fold increased risk of menstrual cycle

irregularities from occupational exposure to antineoplastic drugs [Shortridge et al . 1995]. A study of

Danish oncology nurses showed no stat istically significant differences in birth weight, gestational age,

or sex ratio among exposed moth ers [Skov et al 1992], while a st udy of French oncology nurses found

the mean birth weight of offspring to be lower than those of unexposed pregnancies [Stücker et al 1993].

In summary, although the results of occupational studies vary, they are generally indicative of an

increased risk of adverse reproductive outcomes w ith occupational exposure [Connor et al. 2014]. The

risks seem to be higher with firs t trimester exposure, though there may still be risks with exposure

during the second and third trimeste rs, depending on the specific drug or drugs to which a worker may

be exposed. While none of these st udies were conducted af ter the release of th e NIOSH Alert in 2004,

more recent studies have documented that workplaces ar e still contaminated with these drugs [Schierl et

al. 2009; Connor et al. 2010; Sidero v et al. 2010; Yoshida et al. 2010; Davis et al. 2011; Sessink et al.

2011; Turci et al. 2011; Chu et al. 2012; Polovich and Martin 2011; K opp et al. 2013] and exposures are

most likely still occurring. When these data are consid ered in combination with the results of animal and

patient studies, strong evidence s hows a need for specific guidance for healthcare workers exposed to

antineoplastic and other hazardous drugs in order to adequately protect the reproductive health of

workers and their offspring.



# Recommendations

# 26



# Use	of	Industrial	Hygiene	Practices	to	Reduce	Exposure	to	Hazar dous

Drugs

NIOSH recommends that a workplace be safe for all workers, regard less of their reproductive status,

including workplaces where hazardous drugs are pr esent. Recommendations to protect workers from

occupational exposure to hazardous drugs have been developed by several organizations [OSHA 1999;

NIOSH 2004; ASHP 2006; U SP 2008; ONS 2011]. In general, they a ll adhere to the hierarchy of controls for standard industrial hygi ene practices [Soule 1978] . These recommendations include the proper

use of engineering controls, administrative contro ls, and personal protective equipment [NIOSH 2009].

In addition, training of personnel and other critical work practices are instrumental in protecting workers

from exposure [NIOSH 2004, 2013]. However, NIOSH r ecognizes that current work practices do not

completely eliminate hazardous drug contamination from the workplace, and therefore worker exposure

to these drugs can occur. As noted above, several recen t studies have added to the wealth of earlier information on workplace contamination with antineopl astic drugs. Therefore, employers should use and

maintain the most up-to-date engi neering controls and follow current recommendations in order to reduce as much as possible or elim inate worker exposure to hazardous drugs. These include recommendations from NIOSH, OSHA, ASHP, ONS, USP and other professional or ganizations. Additional information on adverse reproductive effects of these drugs can be found in the drug package inserts and in the

SDS for the drugs. However, on the basis of recent studies of workplace contamination, current engineering controls and other precautions do not comple tely eliminate the potential for worker exposure

and thus may not be enough to protect vulnerable offspring of male and female workers who handle

these drugs.



# Implementation	of	an	Alternative	Duty	or	Temporary	Reassignment

# 27



# Program

Given that a developing fetus and a newborn infant are uniquely vulner able to certain hazardous drugs,

especially antineoplastic drugs, because they are ra pidly developing and thei r metabolic, detoxification

and excretion processes are immature, and given the pot entially devastating impact of such exposures, it

is reasonable to take extra precautions to protec t them [Gonzalez 2011]. One such additional precaution

is to offer employees who are pregnant, breast-feeding, or actively trying to conc eive the option of alternative duty. Alternative duty does not mean the worker is excused from work. It does suggest some reassignment of duties, often within the same job, to avoid handling hazardous drugs. For example, various nursing or pharmacy duties can be redistributed among a team of workers, or the organization of

work can be altered to allow those needing reassignment to still work in many aspects of their jobs. In

some instances, however, a true temporary position re -assignment might be necessary to avoid exposure

to hazardous drugs.

It is estimated that 68% of working women will beco me pregnant at least once during their working life

[Cleveland et al. 2000]. Two-thirds of women work during their first pregnancy, and more than half

(55%) of all births are to worki ng women [U.S. Census Bureau 2010]. Beyond the benefits to the health

of workers and their offspring, providing accommodati ons to expectant and nursing workers may reduce

turnover and increases morale and productivity.

NIOSH reviewed existing policies fr om several professional and govern ment organizations that have

recommendations for alternative duty or temporary re assignment for healthcare workers who may be at

risk of exposure to hazardous dr ugs during critical times in repr oduction (Appendix 5). Typically, these

include times when couples (males and females) ar e actively trying to con ceive and when women are

pregnant and/or breastfeeding. However, conception can be a difficult issue to deal with because approximately 50% of all pregnancie s are not planned [Finer and Zoln a 2006]. Temporary reassignment

# 28

should also be considered when an individual’s medi cal history or risk factors suggest a need for requesting reassignment from working with hazardous drugs based on pe rsonal fertility history and any

other underlying medical conditions that may put a worker at excepti onal risk of harm [ACOEM 2011].

The majority of these policies indica te that the employer should offer al ternative duty and that the worker’s decision to accept it should be voluntary. Sin ce 1995, OSHA has recommended that healthcare facilities have a policy in place regarding reproductiv e risks associated with occupational exposure of

workers to hazardous drugs and that such a polic y should be followed [OSH A 1999]. Some recommendations state that an initial risk assessment should be performed in order to determ ine if there is potential

reproductive harm to the fetus or offspring [HSE 2003; ACOEM 2011]. However, because there are no

established permissible exposure limits (PELs) or other guidance values for these drugs [NIOSH 2004],

a complete risk assessment is usually not possible. N onetheless, workers potentially at risk may be identified by an exposure assessment. In some cases, workers (such as pharmacy personnel, nursing personnel, and housekeeping and waste dispos al personnel) may be identified as at-risk on the basis of their job

classification, indicating their dutie s may potentially expose them to ha zardous drugs. An exposure assessment may also identify other work ers with potential exposure, sinc e studies have shown that wherever hazardous drugs are present in a healthcare facility, environmental contamination is common.

After carefully reviewing animal st udies, human studies of patients a nd workers, and the properties of

hazardous drugs that provide clues about the mechanis tic plausibility of repr oductive risk from exposure, NIOSH recommends that healthcare workplaces where antineoplastic and other hazardous drugs

are present have a policy for alternative duty for expos ed workers who are a reproductive risk [Figure 1].

An alternative-duty or temporar y-reassignment program typically includes the following elements:

 Identifying drugs in the workplace with potential adverse reproductive effects.

 Identifying job functions or tasks that present a potential for exposure to reproductive hazards.

# 29

 Conduct an initial risk assessment for the drugs being used.

 Identifying job functions or tasks that can be safely performed by workers requesting alternative

duty for reproductive issues.

 Developing new-employee and annu al refresher training as part of the management’s hazard

communication program. Training should help hea lthcare workers identify their potential for exposure during their windows of risk. During training, workers s hould be informed that windows

of vulnerability to developmental health typically begin before fertilization or before a pregnancy

is recognized, thus necess itating the provision of al ternative duty during or before actively trying

to conceive.

 Developing mechanisms by which workers who ar e actively trying to conceive, who are pregnant, or who are breast-feeding can reque st alternative duty or reassignment.

Workers should be encouraged to notify their employer of their request for reassignment before their

window of risk, or as soon as possible once risk is recognized, with the unders tanding that such information is confidential. The notification should be done through the employee health unit. If this is not

feasible, then notificatio n should be made through th eir immediate supervisor.



# Medical, Legal and Ethical Issues

The development and implementation of policies for protection of reproductive health involve complex

issues related to both science and law. Safety fr om reproductive hazards and freedom from discrimination on the basis of gender or pregnancy can appear to present conflict or appear intrusive into personal

areas of an employee’s reproductive and health status. When a worker requests alternative duty, confidential information and matters of the employee’s pr ivacy might become known in the workplace [Saiki

et al. 1994]. Because of the legal implications of requests for special accommodations during pregnancy,

# 30

several states have adopted laws that require empl oyers to provide at least some accommodations if requested.

The 1978 Pregnancy Discrimination Act amended Title VI I of the Civil Rights Ac t to include the wording “because of or on the basis of pregnancy, childbi rth, or related medical conditions” in reference to

unlawful employment practices that “...in any way...would deprive or te nd to deprive any individual of

employment opportunities or otherwise adversely affect his [sic] status as an employee...” A woman or

man cannot be denied employment or be removed from employment because of her or his reproductive

status. If an employer provides al ternative duty on the basis of reproductive status in order to limit

workers’ exposure to hazardous drugs, then the polic y will not violate Title VII as long as employees

retain the right to remain in their positions if they choose.

It is important that alternative du ty or other workplace policies intended to protect workers and their offspring do so in a manner that does not discriminate against workers on the basis of gender or other protected characteristics. Forcing an employee to accept alternative duty on the basis of gender or pregnancy is unlawful; alternative duty policies should ther efore be voluntary. Employers may offer voluntary

alternative duty on the basis of reproductive status, ev en if alternative duty is not offered to other employees with temporary disabilities. Offering this ty pe of accommodation should not be seen as an admission on the part of an employer of dangerous condi tions in the workplace. Ra ther, offering the option

for alternative duty should be seen as evidence ofthe employer’s commitment to doing everything possible to assure the well-being of workers and thei r families. Reassigned workers should retain wages,

seniority, and other benefits that mi ght otherwise be lost by a job tran sfer and should not be discriminated against on the basis of their job status.

In preparing an alternative duty po licy, it is important to consider both male and female reproduction

issues equally. Alternative duty pol icies should protect th e reproductive capacity and offspring of both

# 31

male and female workers, although the appropriate type and timing of accommodations may vary.



# Summary

The primary limitation of the studies we evaluated is the era of the data collection; all studies published

to date evaluate data collected prior to 2002, and mo st data were collected in the 1980’s. Though there

has been a lot of attention recently to raise awaren ess of controlling occupational exposure to antineoplastic and other hazardous drugs, studies continue to show that exposures are still occurring. Another

important limitation of the literature is the small sample sizes, particul arly the small numbers of exposed

cases. Because of this limitation, studies were ofte n unable to adjust for c onfounding factors and reported wide confidence intervals. However, most of the studies we reviewed that had larger relative sample

sizes indicated an increased risk of adverse reproductive health out comes. Though there are few studies

of fertility, there appears to be an indication of a ri sk with exposure. Finally, most studies lacked enough

statistical power or proper exposur e assessment to evaluate dose.

Considering the biologic plausibility of the mechan isms of action of many hazardous antineoplastic

drugs, and observations of adverse reproductive and developmental heal th outcomes observed in treated

cancer patients, this review suggests, fairly consistently, that there are also elevated risks to reproductive

health for exposed workers. Workplace contamination studies indicate that hazardous drug exposure is

widespread, commonly occurring duri ng any handling activity, despite us e of current safety guidance.

Therefore, additional precautions to prevent exposure during uniquely vulnerable windows of fetal and

newborn development should be considered.

# 32



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− 38.41Table 1. Studies of Congenital Anomalies Associated withParental Occupational Exposure to Antineoplastic Drugs*ReferenceExposurePeriodStudyLocationPopulationStudyDesignOverallSampleSizeNumberofexposedcasesResultsCommentsFransmanetal.20071990–1997NetherlandsOncology&othertypesofnursesSurvey1,5195inhighestexpo‐surecategoryNosignificantassociations;CIswerewideRetrospectiveexposureassessmentwasbasedonfrequencyoftasks;estimateddermalexpo‐sure.Noevidenceofdoseresponse.Hemminkietal.1985<1985FinlandFinnishhospitalnursesCase–control;survey38cases;99controls19AdjOR,4.7(1.2–18.1)11exposedcaseshandledlessthan1/week;8expocaseshandledonceormoreperweek.McAbeeetal.19931985USNursesanduni‐versityemploy‐eesCross‐sectionalsurvey633women(1,133preg‐nancies)10Oncologynursesreportedmorebirthdefectsthanthecontrolgroup(p=0.02forcrudeanaly‐sis).Responseratewas30%;analyzedfirstpregnan‐ciesseparatelyfromeachadditionalpregnancyMcDonaldetal.19881982–1984MontrealPopulationbased;doctorsandnursesSurvey152exposedpregnancies88/4=observed/expectedUsedmedicalrecordsPeelenetal.1999<1985NetherlandsOncologynursesSurvey229exposed+956unexposed7OR,5.1(1.1–23.6)amongnurseswhopreparedhaz‐ardousdrugsHadtoworkinoncologyfor2monthsormoreduringpregnancyRatneretal.20101974–2000CanadaRegisterednursesSurvey;regis‐try12,74117AdjOR,1.42(0.86–2.36)BasedonRNswhowereeverorneveremployedinoncologySkovetal.19921985DenmarkOncologynursesRetrospectivecohort266exposed+770unex‐posed16AdjOR,1.36(0.59–3.14)inhighestexposurecategoryPreparedoradministeredhazardousdrugsdur‐ingpregnancyLorenteetal.20001989–1992EuropePopulation‐basedCase–control64cleftlip/palate+36cleftpalate+751controls3Cleftlip:OR,3.35(0.37–3.12);Cleftpalate:OR,11.25(1.98–63.7)CIswerewide.*Previously published. Connor et al. 201442Table 2. Studies of Miscarriage, Stillbirth, Tubal Pregnancy Associated with Occupational Exposure to Antineoplastic Drugs*ReferenceExposurePeriodStudyLocationPopulationStudyDe‐signOverallSampleSizeNumberofexposedcas‐esResultsCommentsFransmanetal.20071990–1997NetherlandsOncologyandothertypesofnursesSurvey1,51934,butdividedinto3categoriesNosignificantassociations;CIswerewideformiscarriageSmallnumbersincatagories;samplesizeswerenotclearlyreported.RetrospectiveexposureassessmentamongnursesHemminkietal.1985<1985FinlandFinnishhospitalnursesCase‐control169cases+469controls12AdjOR,0.8(0.3–1.7)formiscar‐riage50%ResponserateLawsonetal.20121993–2001U.S.U.S.registerednursesSurvey775cases+6,707livebirths48AdjOR,1.94(1.32–2.86)formiscarriagePeelenetal.1999<1985NetherlandsOncologynurs‐esSurvey249exposed+1,010unex‐posedUnclearOR,1.4(0.8–2.6)formiscarriageSmallnumbers,limitationsinstudydesign.SeeFransmanstudythatreplacesthisstudy.Selevanetal.1985<1985FinlandNursesCase–control124cases+321controls18OR,2.3(1.21–4.39)formiscar‐riageFirst‐trimesterexposuretohazardousdrugsmorethanonceperweekSkovetal.19921985DenmarkOncologynurs‐esRetrospectivecohort281exposed+809unexposed18AdjOR,0.74(0.40–1.38)formiscarriagePreparedoradministeredhazardousdrugsany‐timeduringpregnancyStückeretal.19901985FranceHospitalper‐sonnelSurvey139exposed+357unex‐posed36AdjOR,1.7(1.03–2.80)formiscarriagePreparedhazardousdrugsValanisetal.19991985U.S.NursesandpharmacistsSurvey1,448exposed+5,297unex‐posed223AdjOR,1.50(1.25–1.80)formiscarriageExposuretohazardousdrugsduringpregnancyMcDonaldetal.19881982–1984MontrealPopulationbasedIn‐personsur‐vey22,6131313observed/13.4expectedmiscarriagesandstillbirthsAdministeredhazardousdrugsduring1sttri‐mesterMcAbeeetal.19931985U.S.NursesanduniversityemployeesCross‐sectionalsurvey663women(1,133preg‐nancies)3AdjORof0.67formiscarriageandstillbirthLowresponserates(<30%)RogersandEmmett1987<1985U.S.OncologyandcommunityhealthnursesSurvey23313OR,2.5(p<0.04)formiscarriageandstillbirthORdidn’tchangewithadjustmentforage43Fransmanetal.20071990–1997NetherlandsOncology&othertypesofnursesSurvey1,5191inthehighestcategoryNosignificantassociations;CIswerewideforstillbirthRetrospectiveexposureassessmentoffrequencyoftasks,dermalexposurePeelenetal.19991990–1997NetherlandsOncologynurs‐esSurvey249exposed+1,010unex‐posed2OR,1.2(0.65–2.20)forstill‐birthSmallnumbersValanisetal.19991985U.S.NursesandpharmacistsSurvey7,09412AdjOR,1.10(0.55–2.20)forstillbirthRatneretal.20101974–2000CanadaRegisterednursesCohort147/23,2223AdjOR,0.67(0.21–2.13)forstillbirthBouyeretal.19981993–1994FranceHospitalper‐sonnelCase‐–control104cases/279controls10AdjOR,0.95(0.39–2.31)fortubalpregnancyStudiedonlypreconceptionexposures.UpdateofSaurel‐Cubizolles1993article.Potentiallyover‐adjusted;includedpreviousSAinanalysis.CIswerewidequestion.Saurel‐Cubizollesetal.19931985ParisHospitalnursesSelf‐administeredsurvey85exposedand599unexposed6AdjOR,11.4(2.7–17.6)fortubalpregnancyExposuretohazardousdrugsduring1sttri‐mester.SeeBouyerupdatefrom1998.*Previously published. Connor et al. 201444Table 3. Studies of Fertility, Time to Pregnancy, Menstrual Function, Birthweight, GestationalAge, and Sex Ratio. Associatedwith Occupational Exposure to Antineoplastic Drugs*ReferenceExposurePeriodStudyLocationPopulationStudyDe‐signOverallSampleSizeNumberofexposedcas‐esResultsCommentsValanisetal.1997<1985U.S.NursesandpharmacypersonnelCase‐control405cases+1,215controls78OR,1.5(1.1–2.0)forinfertilityFransmanetal.20071990–1997NetherlandsOncologyandothertypesofnursesSurvey12626inhighestcategoryHazardratio,0.8(0.6–‐0.9)fortimetopregnan‐cyRetrospectiveexposureassessmentamongnursesShortridgeetal.19951986U.S.ONSandANAmembersSurvey1,458172AdjOR,3.4(1.6–7.3)formen‐strualdysfunc‐tionamongnurseswhoadministeredchemotherapyMenstrualdysfunctiondefinedasoneofthefollowing:a)3+monthsofnoperiods,b)cyclelengthof<25or>31days,orc)flowdurationof<2or>7daysSkovetal.19921985DenmarkOncologynurs‐esRetrospectivecohort266exposed/770unexposed266Nostatisticallysignificantdiffer‐encesinadjustedanalysesbe‐tweenexposedandunexposedforbirthweight,gestationalage,orsexratioStückeretal.19931985–1986FranceOncologynurs‐esSurvey420Singletonlivebirths107exposedpregnanciesInadjustedmodels,meanbirthweightofexposedpreg‐nancieswas56glowerthanun‐exposed(95%CI,minus155.1to43.1)Nodifferenceingestationalagebetweenex‐posedandunexposed*Previously published. Connor et al. 2014Abbreviations used: OR-odds ratio; AdOR-adjusted odds ratio; CI-confidence interval4546Appendix 1. Hazardous Drug (HD) Handling Activities in Healthcare Workers that can Result in ExposureWorkers Potentially Exposed ActivityPharmacists, pharmacy techniciansHandling drug-contaminated vialsReconstituting powdered or lyophilized drugs and further diluting either thereconstituted powder or concentratedliquid forms of hazardous drugsExpelling air from syringes filled with hazardous drugsCompounding HD powders into custom-dosage formsTransferring drug solutionto IV bag or bottle.Pharmacists, pharmacy technicians, nursingpersonnelCounting out individual, uncoated oral doses from multidose bottlesUnit-dosing uncoated tablets in a unit-dose machineCrushing tablets or opening capsules to make oral liquid doseOpening ampoulesPreparing topical drugsNursing personnelAdministering antineoplastic drugs by injection (intramuscular, subcutaneous orintravenous (IV)), by inhalation or by nasogastric tubeSpiking the IV set into an HD-containing IV bag (without a closed system)47Priming the IV set with a drug-containing solution at the administration locationConnecting and disconnecting the IVset to an IV pump or patientNursing personnel, support staff, housekeepingpersonnel, laundry personnelHandling body fluids or body-fluid-contaminated clothing, dressings, linens,bedpans, urinals and other materialsHandling contaminated wastes generatedat any step of the preparation oradministration processPharmacists, pharmacy technicians, nursingpersonnel, housekeeping personnel,environmental services personnelContacting hazardous drugs present on drug vial exteriors, work surfaces, floors,and final drug products (bottles, bags, cassettes, and syringes)Handling unused antineoplastic drugs orantineoplastic drug-contaminated wasteDecontaminating and cleaning drugpreparation or clinical areasCleaning hazardous drug spillsPhysicians, nursing personnel, operating roompersonnelPerforming certain specialized HD administration procedures such asintraperitoneal chemotherapy (in the operating room or other locations), bladderinstillation, isolated limb perfusionSupport staffTransporting hazardous throughout the facilityNursing personnel, housekeeping personnel,waste disposal personnelTransporting hazardous waste containersPharmacists, pharmacy technicians, nursingRemoving and disposing of personalprotective equipment after handling48personnel, housekeeping personnel hazardous drugs or waste49Appendix 2. FDA Pregnancy Categories ofDrugs Listed by NIOSH as Hazardous1Drugs that Should be Handled as HazardousFDAPregnancyCategory2AHFS Pharmacologic-Therapeutic Classification2Abacavir C 8:18.08.20 Nucleoside andreverse transcriptase inhibitorsAbiraterone X 10:00 Antineoplastic agentsAcitretin X 88:04 Vitamin AAdo-trastuzumab emtansine D10:00 Antineoplastic agentsAmbrisentan X 24:12.92 Vasodilating agents, miscellaneousAlefacept B 84:92 Skin and mucous membrane agents, miscellaneousAlitretinoin D 84:92 Skin and mucous membrane agents, miscellaneousAltretamine D 10:00 Antineoplastic agentsAnastrozole X 10:00 Antineoplastic agentsApomorphine C 28:36.20.08 Nonergot-derivative dopamine receptoragonistsArsenic trioxide D 10:00Antineoplastic agentsAzacitidine D 10:00 Antineoplastic agentsAzathioprine D 92:44 Immunosuppressant agentsBacillus Calmette-Guerin(BCG)C 80:12 VaccinesBendamustine D 10:00 Antineoplastic agentsBexarotene X 10:00 Antineoplastic agentsBicalutamide X 10:00 Antineoplastic agentsBleomycin D 10:00 Antineoplastic agentsBortezomib D 10:00 Antineoplastic agentsBosentan X 24:12.92 Vasodilating agents, miscellaneousBrentuximab vedotin D 10:00 Antineoplastic agentsBusulfan D 10:00 Antineoplastic agentsCabazitaxel D 10:00 antineoplastic agents50Cabergoline B 28:36. 20.04 Ergot-derivative dopamine receptor agonistsCapecitabine D 10:00 Antineoplastic agentsCarbamazepine D 28:12.92 Anticonvulsants, miscellaneousCarboplatin D 10:00 Antineoplastic agentsCarmustine D 10:00 Antineoplastic agentsCetrorelix X 92:40 Gonadotropin-releasing hormone antagonistsChlorambucil D 10:00 Antineoplastic agentsChloramphenicol C 8:12.08 ChloramphenicolsChoriogonadotropin alfaX 68:18 GonadotropinsCidofovir C 8:18.32 Nucleosides and nucleotidesCisplatin D 10:00 Antineoplastic agentsCladribine D 10:00 Antineoplastic agentsDrugs that Should beHandled as Hazardous(Continued)FDAPregnancyCategoryAHFS Pharmacologic-Therapeutic ClassificationClofarabine D 10:00 Antineoplastic agentsClonazepam D 28:12.08 BenzodiazepinesColchicine C 92:16 Antigout agentsCrizotinib D 10:00 Antineoplastic agentsCyclophosphamide D 10:00 Antineoplastic agentsCyclosporin C 92:44 Immunosuppressive agentsCytarabine D 10:00 Antineoplastic agentsDacarbazine C 10:00 Antineoplastic agentsDactinomycin D 10:00 Antineoplastic agentsDasatinib D 10:00 Antineoplastic agentsDaunorubicin D 10:00 Antineoplastic agentsDecitabine D 10:00 Antineoplastic agentsDeferiprone D 64:00 Heavy metal antagonistsDegarelix X 10:00 Antineoplastic agentsDexrazoxane C 92:56 Protective agentsDiethylstilbestrol X Not in AHFS (nonsteroidal synthetic estrogen)51Dinoprostone C 76:00 OxytocicsDocetaxel D 10:00 Antineoplastic agentsDoxorubicin D 10:00 Antineoplastic agentsDronedarone X 20:04.04 AntiarrythmicsDutasteride X 92:08 5-alpha reductase inhibitorsEntecavir C 8:18.32 Nucleosides and nucleotidesEpirubicin D 10:00 Antineoplastic agentsEribulin D 10:00 Antineoplastic agentsErlotinib D 10:00 Antineoplastic agentsErgonovine/methylergonovineC 76:00 OxytocicsEstradiol X 68:16.04 EstrogensEstramustine X 10:00 Antineoplastic agentsEstrogen-progestin combinationsX 68:12 ContraceptivesEstrogens, conjugated X 68:16.04 EstrogensEstrogens, esterified X 68:16.04 EstrogensEstropipate X 68:16.04 EstrogensEtoposide D 10:00 Antineoplastic agentsEverolimus X 10:00 Antineoplastic agentsExemestane D 10:00 Antineoplastic agentsFinasteride X 92:08 5-alpha reductase inhibitorsFingolimod C 92:20 Biologicresponse modifiers52Drugs that Should beHandled as Hazardous(Continued)FDAPregnancyCategoryAHFS Pharmacologic-Therapeutic ClassificationFloxuridine D 10:00 Antineoplastic agentsFluconazole C 8:18.08 AzolesFludarabine D 10:00 Antineoplastic agentsFluorouracil D/X310:00 Antineoplastic agentsFluoxymesterone X 68:08 AndrogensFlutamide D 10:00 Antineoplastic agentsFosphenytoin D 28:12.12 HydantoinsFulvestrant D 10:00 Antineoplastic agentsGanciclovir C 8:18.32 Nucleosides and nucleotidesGanirelix X 92:40 Gonadotropin-releasing hormone antagonistsGemcitabine D 10:00 Antineoplastic agentsGemtuzumab ozogamicin D 10:00 Antineoplastic agentsGonadotropin, chorionicX 68:18 GonadotropinsGoserelin X 10:00 Antineoplastic agentsHydroxyurea D 10:00 Antineoplastic agentsIcatibant C 92:32 Complement inhibitorsIdarubicin D 10:00 Antineoplastic agentsIfosfamide D 10:00 Antineoplastic agentsImatinib D 10:00 Antineoplastic agentsIrinotecan D 10:00 Antineoplastic agentsIxabepilone D 10:00 Antineoplastic agentsLeflunomide X 92:36 Disease-modifying antirheumatic agentsLenalidomide X 92:20 Biologic response modifiersLetrozole X 10:00 Antineoplastic agentsLeuprolide X 10:00 Antineoplastic agentsLiraglutide recombinant C 68:20.06 Incretin mimeticsLomustine D 10:00 Antineoplastic agentsMechlorethamine D 10:00 Antineoplastic agentsMedroxyprogesterone X 68:32 Progestins53acetateMegestrol X 10:00 Antineoplastic agentsMelphalan D 10:00 Antineoplastic agentsMenotropins X 68:18 GonadotropinsMercaptopurine D 10:00Antineoplastic agentsMethotrexate X 10:00 Antineoplastic agentsMethyltestosterone X 68:08 AndrogensMifepristone X 76:00 Oxytocics54Drugs that Should beHandled as Hazardous(Continued)FDAPregnancyCategoryAHFS Pharmacologic-Therapeutic ClassificationMisoprostol X 56:28.28 ProstaglandinsMitomycin D 10:00 Antineoplastic agentsMitotane D 10:00 Antineoplastic agentsMitoxantrone D 10:00 Antineoplastic agentsMycophenolate mofetil D 92:44 Immunosuppressive agentsMycolphenolic acid D 92.44 Immunosuppressive agentsNafarelin X 68:18 GonadotropinsNelarabine D 10:00 Antineoplastic agentsNevirapine B 8:18.08.16 Nonnucleosidereverse transcriptase inhibitorsNilotinib D 10:00 Antineoplastic agentsOmacetaxin D 10:00 Antineoplastic agentsOxaliplatin D 10:00 Antineoplastic agentsOxcarbazepine C 28:12.92 Anticonvulsants. MiscellaneousOxytocin C 76:00 OxytocicsPaclitaxel D 10:00 Antineoplastic agentsPalifermin C 84:16 Cell stimulants and proliferantsParoxetine D 28:16.04.20 Selective seretonin uptake inhibitorsPazopanib D 10:00 Antineoplastic agentsPemetrexed D 10:00 Antineoplastic agentsPentetate calcium trisodium C Not in AHFSPentostatin D 10:00 Antineoplastic agentsPhenoxybenzamine C 12:16.04.04 Non-selective alpha-adrenergic blockingagentsPhenytoin D 28:12.12 HydantoinsPlerixafor D 20:16 Hematopoietic agentsPralatrexate D 10:00 Antineoplastic agentsProcarbazine D 10:00 Antineoplastic agentsProgesterone B 68:32 Progestins55Progestins X 68:12 ContraceptivesPropylthiouracil D 68:36.08 Antithyroid agentsRaloxifene X 68:16.12 Estrogen agonists-antagonistsRasagiline C 28:36 Antiparkinsonian agentsRibavirin X 8:18.32 Nucleosides and nucleotidesRisperidone C 28:16.08.04 Atypical antipsychoticsRomidepsin D 10:00 Antineoplastic agentsSirolimus C 92:44 Immunosuppressive agentsSorafenib D 10:00 Antineoplastic agents56Drugs that Should be Handled as Hazardous (Continued)FDAPregnancyCategoryAHFS Pharmacologic-Therapeutic ClassificationSpironolactone C 24:32.20 Mineralocorticoid receptor antagonistsStreptozocin D 10:00 Antineoplastic agentsSunitinib D 10:00 Antineoplastic agentsTacrolimus C 92:44 Immunosuppressive agentsTamoxifen D 10:00 Antineoplastic agentsTelevancin C 8:12.28.16 GlycopeptidesTemozolomide D 10:00 Antineoplastic agentsTemsirolimus D 10:00 Antineoplastic agentsTeniposide D 10:00 Antineoplastic agentsTestosterone X 68:08 AndrogensThalidomide X 92:20 Biologic response modifiersThioguanine D 10:00 Antineoplastic agentsThiotepa D 10:00 Antineoplastic agentsTopiramate D 28:12.92 Anticonvulsants, miscellaneousTopotecan D 10:00 Antineoplastic agentsToremifene D 10:00 Antineoplastic agentsTretinoin C/D384:16 Cell stimulants and proliferantsTriptorelin X 10:00 Antineoplastic agentsUlipristal X 68:12 ContraceptivesUracil mustard D N/AValganciclovir C 8:18.32 Nucleosides and nucleotidesValproic acid/divalproex Na D28:12.92 Anticonvulsants. MiscellaneousValrubicin C 10:00 Antineoplastic agentsVandetanib D 10:00 Antineoplastic agentsVemurafenib D 10:00 Antineoplastic agentsVigabatrin C 28:12.92 Antinconvulsants, miscellaneousVinblastine sulfate D 10:00 Antineoplastic agentsVincristine sulfate D 10:00 Antineoplastic agentsVinorelbine tartrate D 10:00 Antineoplastic agents57Voriconazole D 8:14.08 AzolesVorinostat D 10:00 Antineoplastic agentsWarfarin D 20:12.04.08 Coumarin derivativesZidovudine C 8:18:08 Antiretroviral agentsZiprasidone HCl C 28:16.08.04Atypical antipsychoticsZoledronic acid D 92:24 BoneresorptioninhibitorsZonisamide C 28:12.92 Anticonvulsant, miscellaneous1NIOSH 20142ASHP/AHFS 20123Varies with formulation58Appendix 3. FDA-Assigned Pregnancy Categories1FDA Pregnancy Category DescriptionAAdequate and well-controlled studies have failed todemonstrate a risk to the fetus in the firsttrimester of pregnancy (and there is no evidence of risk in later trimesters).BAnimal reproduction studies have failed to demonstrate a risk to the fetus and there are noadequate and well-controlled studies in pregnant women.CAnimal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studiesin humans, but potential benefits may warrant use of thedrug in pregnant women despite potential risks.DThere is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies inhumans, but potential benefits may warrant useof the drug in pregnant women despite potential risks.XStudies in animals or humans have demonstrated fetal abnormalities and/or there is positiveevidence of human fetal risk based on adversereaction data from investigational or marketing experience, and the risks involved in useof the drug in pregnant women clearly outweighpotential benefits.1Briggs et al. 2008; 21 CFR 201.57(c)(9)(i)59Appendix 4.Databases reviewed: Canadiana, CINAHL, CISILO, DTIC, Embase, Health & Safety Science Abstracts, HSELine,NIOSHTIC-2, NTIS, OSHLine, PubMed, RiskAbstracts, Toxicology Abstracts, Toxline, Web of Science, and WorldCat.PubMed search terms: Antineoplastic agents/adverse effects, antineoplastic agents/prevention and control, Cytotoxins,Hazardous Substances/adverse effects, Hazardous Substances/toxicity, Pharmaceutical Preparations/adverse effects,antineoplastic, cytotoxic, cytostatic, chemotherap*, and Personnel,Hospital, Health Personnel, and Occupational Exposure, Occupational Diseases, Environmental Exposure, occupational, and Reproduction, Infertility, Fertility, PregnancyComplications, pregnan*, infertility, reproducti*. In addition, the following terms were included in searching text:antineoplastic , chemotherapeutic, cytotoxic, cytostatic, pregnan*, infertility, reproducti*, and occupational.60Appendix5.ReproductiveHealthRecommendationsforAlternativeDutyPracticesOrganizationandTopicReproductiveHealthRecommendationsNational Study Commissionon Cytotoxic Exposure.Recommendations for Handling Cytotoxic Agents[1987].There are substantial data regarding the mutagenic, teratogenic,and abortifacient properties ofcertain cytotoxic agents, both in animals and inhumans who have receivedtherapeutic doses ofthese agents. Additionally, the scientific literature suggests a possible association of occupational exposure to certain cytotoxic agents during the first trimester of pregnancy with fetal lossor malformation. These data suggest the needfor caution when women who are pregnant, orattempting to conceive, handle cytotoxic agents.. . . it is prudent that women who are breastfeeding should exercise caution inhandling cytotoxic agents. . .. Personnel should be providedwith information to make an individual decision.This information should be provided in written form and it is advisable that a statement ofunderstanding be signed. .. . It is essential torefer to individual state right-to-know laws to ensure compliance.European Agency for Safetyand Health at Work [1992].Directive 92/85/EEC: pregnant workers.Pregnant and breastfeeding workers may under nocircumstances be obliged to perform dutiesfor which the assessment has revealed a risk ofexposure to agents, which would jeopardizetheir safety or health. Those agents and working conditions are defined in Annex II of the Directive.Women must not be dismissed from work becauseof their pregnancy and maternity for the period from the beginning of their pregnancy tothe end of the period of leave from work.Occupational Safety andHealth Administration(OSHA). OSHA TechnicalManual, TED 1−0.15A, SecVI Chapter 2: Categorizationof drugs as hazardous.The examining physician should consider the reproductive status of employees and informthem regarding relevant reproductive issues.The reproductive toxicityof hazardous drugsshould be carefully explained to all workers whowill be exposed to these chemicals, and [thisaction] is required for those chemicals covered by the HCS [hazard communication standard].Unfortunately, no information is available regarding the reproductive risks of HD [hazardousdrug] handling with the currentuse of BSCs [biological safetycabinets] and PPE [personalprotective equipment]. However, as discussedearlier, both spontaneousabortion and congenital malformation excesses have been documented among workers handling some of these drugswithout currently recommended engineering controls and precautions. Thefacility should havea policy regarding reproductive toxicity of HDsand worker exposure in male and female employees and should follow that policy.61Health and Safety Executive,United Kingdom (HSE)[2003]. New and expectantmothers at work; a guide tohealth professionals.The law requires every employer to assess workplace risks for all their employees, and takepractical action to control those risks. In addition, employers must take particular account ofrisks to new and expectant mothers. The definition of a new or expectant mother is someonewho is pregnant, has given birth within theprevious six months, or is breastfeeding.Employers must identify hazards in their workplacethat could pose a health or safety risk tonew and expectant mother and take appropriate action to remove or reduce the risk. They mustalso make this information known to all their female employees of childbearing age, not justthose who have informed them they are pregnant. This is particularly important for expectantmothers, as it is possible for the first 4−6 weeks of pregnancy to go undetected.If risks are identified go beyond the level of risk found outside the workplace, but cannot beremoved, employers should adjust the woman’s working conditions or hours. If there is still arisk, she must be offered suitable alternative workor, if that is not possible, suspended on fullpay for as long as is necessary toprotect her and her child’s health.American Society of HealthSystem Pharmacists (ASHP)[1990]. ASHP guidelines onhandling hazardous drugs.Because reproductive risks have been associatedwith exposure to hazardous drugs, alternativeduty should be offered to individuals who are pregnant, breast-feeding, or attempting to conceive or father a child. Employees’ physiciansshould be involved in making these determinations.BC Cancer Agency [2008].Safe handling of hazardousdrugs. In: BC cancer agencypharmacy practice standardsfor hazardous drugs.It is the responsibility of the employee handling HDs [hazardous drugs] to discuss with theirimmediate supervisor any desired change in work assignment asa result of their pregnancy,breast-feeding, or attempt to reproduce. All attempts should be made by management to reassign personnel who are pregnant, , or planningimminent parenthood to work in another areaof the pharmacy in order to avoid working directly with hazardous drugs, if so requested.Canadian Association ofPharmacy in Oncology(CAPhO) [2009]. Standardsof Practice for OncologyPharmacy in Canada. November (Version 2).Employees who are pregnant, attempting to conceive or father a child, or are breast feedingmay request to be transferred to alternateduties which do not involve handling hazardousdrugs. A policy should exist to provide direction for personnel in these situations.American College of Occupational and EnvironmentalMedicine (ACOEM) [2011].Reproductive and Developmental Hazard Management...temporary reassignment should be recommended ifthe conclusion of the risk assessment isthat there is exposure to a reproductive or developmental toxicant that cannot be adequatelycontrolled through engineering orwork practice controls alone.Assignment of women who are breast feeding to positions where there are exposures thatwould result in an infant receiving a chemical intakein excess of the acceptable daily intake for62Guidance. that agent should be closely assessed.Oncology Nursing Society(ONS) [2009]. Chemotherapy and Biotherapy Guidelines and Recommendationsfor Practice.Employers should allow employees who are actively trying to conceive or are pregnant orbreast feeding to refrain from activities that may expose them and theirinfant to reproductivehealth hazards such as chemical, physical, orbiologic agents. Alternative duty that does notinclude HD [hazardous drug] preparation or administration mustbe made available upon request to both men and women in the aforementioned situations or who have other medical reasons for not being exposed to HDs.American Nurses Association (ANA) [2012]. American Nurses Association’sHouse of Delegates, Reproductive Rights of RegisteredNurses Handling HazardousDrugs.Advocate that it is essential for all health carefacilities to educate nurses who handle hazardousdrugs about the risk of reproductive and developmental effects thathave been associated withthese drugs; andActively advocate for the right ofnurses to engage in alternative duty that does not requirehazardous drug handling when trying to conceive, when pregnant, and when breastfeeding.U.S. Department of the Army [2013]. OccupationalHealth and Industrial Hygiene Guidance for the Management, Use and Disposalof Hazardous Drugs....HCWs [healthcare workers] who are pregnant, breast-feeding,or are trying to conceive achild should be given the optionof being transferred to other comparable duties that do not involve handling HDs.

# 63

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