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This section addresses procedures for the safe handling of select carcinogens, suspect carcinogens, investigational drugs (INDs), and hazardous drugs (HDs). Table 12.11.1 lists these agents and their primary hazards, but it is not an exhaustive list. To use an agent not listed in the table in an animal study, you must inform EH&S of the agent to be used and include appropriate handling procedures in your IACUC application or modification to determine the appropriate handling procedures. Select carcinogens require the completion of a Carcinogen Memorandum of Understanding and Agreement (CMUA). See Section 4 for a description of the CMUA and Section 2.1 of this chapter for a definition of an authorized CMUA holder.

A select carcinogen is a chemical classified as:

  1. Carcinogenic to Humans, Group 1, by the International Agency for Research on Cancer (IARC); or
  2. A Known Carcinogen (KC) by the National Toxicology Program (NTP); or
  3. A Regulated Carcinogen under the Washington Industrial Safety and Health Act (WISHA).

In addition to carcinogens identified by the IARC, NTP, and WISHA, the table includes select carcinogens that meet the following criteria:

A chemical is classified as a select carcinogen if it is listed under IARC Group 2A, "probably carcinogenic to humans," or under 2B, "possibly carcinogenic to humans," or under the category "reasonably anticipated to be a carcinogen" by NTP, and causes a statistically significant tumor incidence in experimental animals under the following criteria:

  1. Inhalation exposure of six to seven hours per day, five days per week, for a significant portion of a lifetime to dosages of less than 10 mg/cubic meter; or
  2. Repeated skin application of less than 300 mg/kg of body weight per week; or
  3. Oral dosages of less than 50 mg/kg of body weight per day.

Suspect Carcinogens are defined as those agents listed as IARC Group 2A, "probably carcinogenic to humans," or 2B, "possibly carcinogenic to humans," or under the NTP category "reasonably anticipated to be a carcinogen."

Hazardous drugs include those drugs as defined by the Federal Food, Drug, and Cosmetic Act that are not handled in a solid final form (capsules, tablets, pills) suitable for direct administration, and have one or more of the characteristics considered hazardous by WISHA.

According to WISHA's Hazard Communication Standard, agents with one or more of the following characteristics are considered hazardous:

  1. Carcinogens;
  2. Corrosives;
  3. Toxic, Highly Toxic or Dangerously Toxic based on the LD50;
  4. Irritants;
  5. Sensitizers; or
  6. Target organ effectors, including reproductive toxicants, hepatotoxins, nephrotoxins, neurotoxins, agents that act on the hemopoietic system, and agents that damage the lungs, skin, eyes or mucous membranes.

Note: Both human and animal data are used for this determination.

An investigational drug or test agent is an agent used in research and not regulated as a drug by the Federal Food, Drug, and Cosmetic Act. These agents generally have limited standard toxicological information available. These agents must be handled with care until studies show otherwise.

At the Fred Hutch , the chemical is considered hazardous until data proves otherwise.

The four handling procedures listed in Table 12.11.1. are explained after the table.

Use this Table 12.11.1 to identify:

  1. Which agents require completion of a CMUA;
  2. Which procedures must be used when working with the agent;
  3. The hazard status of an agent; and
  4. WISHA carcinogens.

Table 12.11.1 is a summary of suspect and select carcinogens classified using the standard occupational health and toxicological references below. The table also includes INDs and HDs either identified by EH&S or used at Fred Hutch. References used to classify these substances are:

  • Annual Report on Carcinogens (11th Report). National Toxicological Program (NTP), U.S. Department of Health & Human Services. 2005.
  • IARC Monograms (latest edition, 2000). International Agency for Research on Cancer Monograms (IARC), World Health Organization. 2000.
  • Washington State Administrative Code (WAC) 296-62-073. Washington Industrial Safety and Health Administration (WISHA).

This table is not exhaustive. If you are using an agent not listed in Table 12.11.1 for research involving the use of animals, notify EH&S to discuss the handling procedures required. Be sure to include the safe handling procedures in the IACUC application or modification. Other toxicology information is provided as needed and as available.

Column two clarifies which agents require the PI or supervisor to submit a Chemical Carcinogen Memorandum of Understanding and Agreement (CMUA).

Column three lists the safe handling procedures required when using the agent. The fourth column lists the principle hazard of the agent as follows:

  • The letter C is used to denote a chemical that has shown carcinogenic tendencies.
  • The letter S is used to identify those agents that are considered suspect carcinogens in humans.
  • The letter H is used to identify those agents that are considered hazardous drugs as defined by WISHA. NIOSH has published a list of common Hazardous Drugs in Appendix A of Publication #2004-165 Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings.
  • The letter I is used to identify those agents that are considered investigational agents or agents with insufficient toxicological information available to determine the hazard potential. These agents have the highest-level handling requirements to protect the health of employees handling these agents and the technicians caring for the animals in the study.

The last column identifies those agents listed by WISHA that require notification of use to Labor and Industries, medical surveillance for users, exposure monitoring as well as the completion of the CMUA.

Table 12.11.1

Refer to Table 12.11.1 for a list of agents and their primary hazards, but it is not an exhaustive list.

12.11.1 Procedure 1 - Handling Procedures for Suspect Carcinogens

This procedure should be followed for suspect carcinogens. When using large quantities of suspect carcinogens, EH&S recommends the use of Procedure 12.11.2 instead.

Employees handling the substance must know the health and physical hazards, routes of exposure, and how to use appropriate protective equipment.

  1. Protect hands and forearms by wearing non-powdered gloves, safety glasses, and a buttoned lab coat to avoid contact of the substance with skin. No skin should be exposed between the gloves and forearms.
  2. Wash hands and arms immediately after working with the substance.
  3. If aerosols are created during the work, or if the substance is volatile, perform the work inside a chemical fume hood or other suitable containment device (e.g., glove box).
  4. Anticipate vapors being released from apparatus and attach a trap, filter, or condenser as appropriate.
  5. Line work surfaces with removable plastic-backed absorbent paper if working outside a containment device.
  6. Restrict access to the work area and post a warning sign indicating that a potential carcinogen is in use (e.g., Warning-Suspect Cancer-Causing Agent In Use).
  7. Do not evaporate waste in the chemical fume hood. Refer to Chapter VI, Hazardous Waste Directory, for specific disposal information. Evacuate room if a spill occurs outside of the chemical fume hood and call EH&S.
  8. Keep the container sizes and quantities in the work area as small as possible.
  9. Double-contain carcinogens in chemical-resistant trays and mount lab instruments above pans or trays to contain spills. All pans and trays must be chemically resistant.
  10. Review storage, disposal, and emergency response procedures at the end of this section.

12.11.2 Procedure 2 - Handling Procedures for Select Carcinogens

Review and follow all steps in Procedure 12.11.1. In addition:

  1. The principal investigator (PI), supervisor, or lab safety coordinator (LSC) must review and approve all plans for the experiment and disposal of waste.
  2. The PI or LSC must notify the Chemical Hygiene Officer (CHO) at EH&S of plans to use the carcinogen by submitting of a Chemical Carcinogen Memorandum of Understanding and Agreement (CMUA). The CMUA requests general information about the proposed experiment(s), agents in use, handling procedures for the material, emergency response, and disposal procedures. The CHO reviews this information to ensure that the agent or agents are being handled safely and that personal protective equipment and engineering controls are adequate. The CHO may require additional precautions if necessary.
  3. If an employee uses the carcinogen more than once a month, EH&S will determine if medical surveillance is needed. This monitoring will include documentation of the quantities of the carcinogen used and any exposure experienced, worksite air sampling or other testing by EH&S, and medical testing as prescribed by the physician.
  4. All work with the carcinogen must be performed in a controlled area. A controlled area is a lab, a portion of a lab, a chemical fume hood, glove box, etc., designated for use of this material. The control area must be labeled with a warning sign such as Warning-Cancer-Causing Agent In Use, and access to the control area must be limited. All persons in the lab must be made aware of the hazards of the substance and of the precautions they should take during its use. Other work in the controlled area cannot resume until all surfaces have been thoroughly cleaned.
  5. If a glove box is used, the ventilation rate in the glove box should be at least two volume changes per hour (2ACH) and the pressure should be at least 0.5 inches of water lower inside the glove box than outside (negative pressure). If vapors are released, they must be exhausted into the chemical fume hood. It is recommended that vapors be trapped, filtered or condensed before being exhausted into the chemical fume hood.
  6. Lab vacuum pumps used with a carcinogen must be protected by filters and vented into a chemical fume hood. Decontamination of vacuum pumps should be done inside the chemical fume hood. Vacuum lines must be protected with a HEPA filter.
  7. In addition to gloves, safety glasses, and lab coats, other protective apparel may be deemed necessary by the worker, lab supervisor, PI, or by the CHO. Extreme caution should be used when handling large amounts.
  8. When leaving the controlled area, remove all protective clothing and immediately wash hands, forearms, face and neck. Any disposable protective apparel or disposable equipment that is contaminated with the substance must be disposed of as hazardous waste and clearly labeled as carcinogenic. Non-disposable apparel and equipment should be thoroughly washed before being removed from the controlled area.

12.11.3 Procedure 3 - Handling Procedures for Animal Experiments using Hazardous Drugs, Investigational Drugs, Select Carcinogens, or Suspect Carcinogens

Animal studies involving the use of select carcinogens, hazardous drugs HDs, or INDs must comply with the following procedures. Agents identified as select carcinogens also require the completion of a CMUA by the PI or supervisor prior to use. See Table 12.11.1 for a list of agents that require the completion of a CMUA. Frequent (more than one time per month) use of a carcinogen may require medical monitoring.

The lab will handle the agents mentioned above in accordance with standard good lab practices and the following procedures: Drug Preparation and Administration

The PI or a knowledgeable appointee must train workers who handle the drug or chemical to understand the physical properties of the substance, and must give workers the results of experimental studies that show any effects on health and any human data that may be available. If toxicological information is limited, then toxicological data from similar compounds should be reviewed. Employees handling the drug or chemical must be informed of the possible routes of exposure (e.g., inhalation, skin absorption, injection) and proper use of personal protective equipment and engineering controls. A summary of this information and the material solubility must be supplied to Animal Health Resource (AHR) technicians caring for the animals.

The following procedures must be followed for agent preparation:

  1. Employees must be trained in hazard and safe handling procedures.
  2. Employees handling or working with the agent should know the location of the nearest eyewash.
  3. All containers must be labeled with the name of the agent, concentration, hazard warnings, protective measures, and, where appropriate, the date and the preparer's initials.
  4. Protect hands and forearms by wearing gloves, safety glasses, and a buttoned lab coat to avoid contact of material with skin. No skin should be exposed between the gloves and forearms.
  5. Wash hands and forearms thoroughly after working with the substance.
  6. Perform the work inside a chemical fume hood, externally vented biosafety cabinet, or other suitable containment device. If aerosol and dust cannot be controlled by work practice or engineering controls, contact EH&S to be fitted with a National Institute for Occupational Safety and Health (NIOSH) approved respirator. Agent Administration

Steps 1-5 listed in Section 12.11.2 should be followed during agent administration. A chemical fume hood or exhausted BSC is required during administration only if the agent is volatile or aerosolization is likely.

When the material is given via injection or gavage, syringes and IV sets with Luer-lock fittings should be used whenever possible. Priming can be performed into a sterile, alcohol-dampened gauze sponge. Do not prime sets or syringes into the sink or any open receptacle.

All animals must be housed in micro-isolator cages.

If the hazardous drug or chemical carcinogen must be administered in the diet, a closed caging system must be used. Mix all diets containing the material in closed containers inside a chemical fume hood or Class II, Type B2 biological safety cabinet (i.e., vented cabinet). Precautions for Animal Care Technicians

Animal handlers must wear gloves to prevent skin contact when performing work (changing bedding, handling animals etc.) with animals used in studies. The use of non-latex gloves is also recommended. Remove gloves and wash hands and arms thoroughly when work is complete. No other special precautions are generally needed to handle the animals, bedding, or cages. Animal Studies: Cleaning Cages and Bedding

Excreta from animals should be considered contaminated up to 48 hours following drug administration.

Dogs: Animal handlers must wear rubber boots and aprons while cleaning cages. When cleaning the cages avoid creating an aerosol. This can be done by rinsing water down the cage room wall or backsplash to dilute the excreta prior to spraying the area directly to clean the cages.

Small rodents: When cleaning rodent cages, wet the bedding to minimize dust and dispose of it with other bedding. Cages should be cleaned and disinfected as usual.

12.11.4 Procedure 4 - Handling Procedures For WISHA-Regulated Carcinogens

Under WAC 296-62-073 Carcinogens, work involving any amount of the following carcinogens must comply with the requirements below.

  • 2-Acetylaminofluorene
  • Alpha-Naphthylamine
  • 4-Aminodiphenyl
  • Benzidine
  • Beta Naphthylamine
  • Beta-Propiolactone
  • Bis-Chloromethyl ether
  • Dichlorobenzidine (and its salts)
  • 4-Dimethylaminoazobenzene
  • Ethyleneimine
  • Methyl chloromethyl ether
  • Methylene bis (2 - chloroaniline)
  • 4-Nitrobiphenyl
  • N-Nitrosodimethylamine

In addition, the following six carcinogens each have a specific set of regulations governing their use under 296-62-07329 through 296-62-07447. Air monitoring is required to document exposures for these chemicals. EH&S must be contacted prior to using the following chemicals:

  • Acrylonitrile
  • Cadmium
  • 1,2-Dibromo-3-chloropropane
  • Ethylene oxide
  • Inorganic arsenic
  • Vinyl Chloride

The PI or supervisor authorizes a specific worker or workers to perform procedures using the carcinogen. Unauthorized workers are not permitted to perform such work.

All work with the carcinogens above will be performed in accordance with this section and the following requirements:

  1. Prior to working with the carcinogen, the authorized employee must have a baseline medical exam. Periodic exams are required at least annually for as long as the employee works with the carcinogen. The primary purpose of this medical monitoring is to investigate for possible conditions of increased risk, including reduced immunological competence, steroid or cytotoxic therapies, pregnancy, and cigarette smoking. See Section 11.2, Medical Surveillance.
  2. All procedures involving the carcinogens above must be performed within a closed system (e.g., in a chemical fume hood or glove box equipped with charcoal and/or HEPA filters).

12.11.5 Storage of Carcinogens

All containers must be labeled Carcinogen. Volatile carcinogenic agents must be stored with Group 2: Volatile Poisons inside a secondary tray or container (i.e., it must be double-contained) of sufficient capacity to contain all of the material should the primary container leak or break. Label the container with a warning of the material's carcinogenic potential. See Section 9, Proper Chemical Storage.

12.11.6 Disposal of Carcinogens

Excess study solution and materials grossly contaminated with the study material must be labeled and packaged by the researcher for pickup and disposal by EH&S.

Contaminated bedding must be removed in a manner that controls the generation of dust. This can involve wetting the bedding or using a High Efficiency Particulate Air (HEPA) filtered dump station.

If the material is water soluble, animal cages can be washed as usual and re-used in future studies. However, if the material is not water-soluble, AHR and the researcher should determine if the current wash method is sufficient to decontaminate cages.

Animal carcasses used in these studies can be disposed of as standard regulated medical waste.

12.11.7 Emergency Response: Exposure

Overt contamination of gloves or gowns, or direct skin or eye contact should be treated as follows:

  1. Immediately remove gloves, gown, or contaminated clothing. Contaminated items should be collected in a plastic bag labeled Carcinogen.
  2. Wash the affected skin area immediately with soap (not germicidal cleaner) and copious amounts of water. Continue to rinse affected area for 15 minutes.
  3. For eye exposure, immediately flood the affected eye with copious amounts of water using the eyewash for at least 15 minutes.
  4. If inhaled, remove to fresh air.
  5. If swallowed, wash mouth out with water if victim is conscious. Contact the poison control center for ingestion incidents.
  6. Call EH&S and complete an Accident-Illness Report Form as soon as possible and mail to the EH&S at J3-200.
  7. Seek medical evaluation for eye exposure or injurious skin exposure.
  8. Do not take contaminated clothing home. Fred Hutch will clean or replace contaminated clothing.
  9. If life threatening or serious medical emergency, call 9-1-1, then Security x6000, then EH&S x4866.

12.11.8 Emergency Response: Spills

Spills within the chemical fume hood or other containment should be cleaned immediately by lab staff responsible for handling carcinogens. Follow the procedures below:

  1. Wear gown/lab coat, double gloves, and eye protection.
  2. Wipe liquids with absorbent material.
  3. Wipe solids with wet absorbent material.
  4. Clean spill area three times with detergent solution, then rinse with clean water.
  5. Solid waste must be collected in a clear bag labeled Carcinogen for EH&S pickup.
  6. Glass fragments or other contaminated sharps must be disposed of in a sharps container, which is then bagged in a cytotoxic (clear) waste bag with the other materials contaminated in the spill response.

Spills greater than 200 ml or a spill of a volitile carcinogen that occur outside a glovebox or chemical fume hood should be cleaned up by EH&S if lab is not prepared with adequate PPE to respond safely. In the event of a spill:

  1. Evacuate the immediate area.
  2. Post a Warning: Chemical Spill, Do Not Enter sign and lock entries or post a responsible person (or guard) to ensure that no one is inadvertently exposed.
  3. Follow procedure 1-6 above or contact EH&S immediately to request hazardous materials response. After business hours, call Security at 6000 who will contact EH&S.