Using the TTC concept to define acceptable levels of exposures to genotoxic drugs in healthcare settings

The TTC concept was originally proposed to assess the risk of human exposure to poorly investigated chemicals and to define acceptable limits of intake for such compounds [14,15,16]. During the last decades, the TTC concept was frequently modified to cover various toxicological endpoints including (genotoxic) carcinogenicity [11]. Regarding this endpoint, the TTC concept is based on a large dataset of TD50 values (doses resulting in a 50% tumour incidence in animal studies) of known carcinogens. Using a simple linear extrapolation, Kroes et al. defined intakes that correspond to an excess lifetime cancer risk of 1 additional cancer case in 1.000.000 exposed individuals [17]. For the vast majority of compounds the acceptable daily intake was set to 0.15 μg/day for the lifetime exposure to a poorly investigated chemical. Certain high potency genotoxic carcinogens such as aflatoxin-like compounds, N-nitroso-compounds and azoxy-compounds were exempt from the scope of the TTC concept, since they are expected to show carcinogenic effects at or below a daily intake of 0.15 μg/day [17]. Other compounds not covered by the TTC-approach are metals and proteins, that were not included in the initial database to calculate the TTC by Munro (1996) as well as highly bioaccumulative compounds such as polyhalogenated dibenzo-p-dioxins,-dibenzofurans and –biphenyls [15, 17]. We therefore reviewed the chemical structure of 116 common antineoplastic drugs listed in Table 1 of the current NIOSH list of antineoplastic and other hazardous drugs for the presence of exclusion criteria [12]. Ten drug molecules contain metals (arsenic, platinum) or proteins ((conjugated) monoclonal antibodies) and are not covered by the TTC-approach. Seven of the remaining drug molecules were classified as carcinogens (Cat. 1) and 13 as carcinogens (Cat. 2A/B) by the International Agency for Research on Cancer (IARC). A group of three molecules (carmustine, lomustine and streptocin) triggered the structural alert for high potency carcinogenicity (N-nitroso-compounds). The TTC-based risk assessment cannot be applied to these substances. In conclusion, the TTC-concept is generally applicable to the vast majority antineoplastic drugs with the exclusion of metals and proteins and after careful consideration of structural alerts for high potency carcinogenicity. Today, the TTC concept is widely accepted and applied in various regulatory settings such as food and drug safety [10, 38]. In 2018, the European Medicines Agency (EMA) published the latest version of an ICH-guideline on the assessment and control of genotoxic impurities in drugs. The ICH M7 (R1) guideline defines safe maximum levels for undesired genotoxic impurities in drugs to prevent patients from suffering treatment-associated cancer. Based on the linear extrapolation of the TTC concept, the ICH M7 guideline defines a tenfold increased maximum intake of 1.5 μg per day accepting one additional cancer case in 100.000 patients at daily lifetime exposure (70 years) to a genotoxic drug impurity. The excess lifetime cancer risk of 1 additional cancer case per 100.000 treated patients was accepted in favour of the health benefit resulting from the treatment. Based on these assumptions, ICH calculated acceptable daily intakes (ADI) for individual drug impurities for different treatment durations from less than 1 month (ADI 120 μg/day) to lifetime exposure (1.5 μg/day). For multiple impurities, the ADI for lifetime exposure was set to 5 μg/day. In summary, the ICH approach addresses the problem of long-term low dose exposures to genotoxic chemicals based on a very conservative risk model using simple linear extrapolation to different exposure scenarios.

Table 1 Review on hazardous drug contamination of surfaces in healthcare settings. Analytes include 5-FU 5-fluorouracil, CP Cyclophosphamide, DX Docetaxel, GM Gemcitabine, IF Ifosphamide, MT Methotrexate, PX Paclitaxel, Pt Platinum compounds. Note: Pt-compound are not covered by the TTC-concept

In contrast to patients, (health) workers do not experience health benefits from the exposure to hazardous drugs. However, it is widely accepted that the workplace is not a zero-risk environment. For example, in German occupational safety and health legislation, occupational exposure to a carcinogenic chemical is accepted up to an excess lifetime cancer risk of 4 additional cancer case in 100.000 workers (see Technical Rule for Hazardous Substances (TRGS) 910) [39]. This acceptable risk is considerably lower than the decision point for an ‘acceptable’ lifetime cancer risk of 1 additional cancer case in 10.000 workers in the European Union and other regions [40]. Risk-related occupational exposure limits can be derived, when sufficient toxicity data are available [39]. In the absence of sound toxicity data, however, it seems feasible to transfer the patient safety oriented ICH risk assessment approach to the evaluation of cancer risks associated with the occupational exposure of health workers to genotoxic drugs.

As the TTC concept is based on a linear extrapolation of cancer risks, it can easily be adjusted to different settings. We take an ADI of 1.5 μg/day (excess lifetime cancer risk of 1:100.000) from the ICH approach as point of departure (POD) for an acceptabe level of exposure. An ADI of 1.5 μg/day corresponds to a maximum lifetime intake (MLI) of 38,325 μg of genotoxic drug contaminants assuming daily exposure during 70 Years (25,550 days of exposure). Occupational exposure of healthcare staff handling genotoxic drugs usually takes place during a shorter timeframe (usually less than 40 Years). Consequently, the ADI can be adjusted using Formula 1:

$$ ADI\ \left(\mu g/ day\right)=\frac\ (days)} $$

(1)

With ADI = Acceptable daily intake (μg/day)

MLI = Maximum lifetime intake (μg)

tEx = Lifetime exposure days

Assuming an average working life of 40 years (240 exposure days/year) the ADI for drug handling health workers can be set to 4 μg/day without changing the excess lifetime cancer risk of 1 additional work related cancer case in 100.000 workers. Formula 1 can be adjusted for different cancer risks e.g. to fit regional (regulatory) requirements. Using formula 2, an adjusted ADI of 16 μg/day results from the application of an acceptable lifetime excess cancer risk of 4:100.000 as stated in German occupational safety and health legislation. Anyhow, we continue our risk assessment with the conservative assumption of an ADI of 4 μg/day.

$$ _\ \left(\mu g/ day\right)=\frac\ (days)}\times \frac}} $$

(2)

With ADIAdj = Acceptable daily intake (μg/day)

MLI = Maximum lifetime intake (μg)

tEx = Lifetime exposure days

ECRDef = Default excess cancer risk of 1:100.000

ECRAdj = Adjusted excess cancer risk e.g. 4:100.000

Occupational exposure to hazardous drugs in healthcare settings

Health workers may be exposed to hazardous drugs performing various tasks such as unpacking, dose preparation in the pharmacy and administration on the hospital ward. Exposure to genotoxic drugs may also occur during waste handling or following contact to urine and other body fluids of patients under (high dose) therapy. The vast majority of hazardous drugs arrive at the healthcare facility as solutions ready for infusion or as powder to be reconstituted for intravenous administration. (Coated) tablets play a minor role in cancer treatment and exposure of healthcare staff to the API can be neglected as long as the tablet is administered undamaged. Drug exposure may occur by inhalation or oral intake of airborne dust and particles or through dermal contact to contaminated surfaces or devices. In modern healthcare settings, strict safe handling guidelines are in force to reduce potential exposures to hazardous drugs to a reasonable minimum [3]. Hazardous drugs are usually handled using a variety of protective measures such as drug safety cabinets for preparation, chemo spikes and gloves. It can be assumed that the use of safety cabinets prevents any inhalative or oral exposure to airborne drug dust and particles [41]. Outside of drug safety cabinets, hazardous drugs are handled as aqueous solutions only and inhalative or oral exposure is unlikely [42]. The inhalative exposure to hazardous drugs is also neglectable, when cytotoxic drugs are aerosolized on purpose to be intraperitonealy administered during surgeries [37]. Dermal exposure therefore seems to be the most relevant route of exposure of healthcare staff to hazardous drugs. It may occur, if the unprotected skin (hands) of staff gets in contact with contaminated surfaces or accidentally spilled drug solutions.

The aforementioned principle considerations are in line with the results of our recent review of scientific publications on hazardous drugs exposure in healthcare settings. A PubMed database request returned a total of 70 original publications and reviews (see methods part for details). The vast majority of studies addressed the dermal exposure and the contamination of surfaces with hazardous drugs (n = 37). Inhalative exposure was studied in seven publications. Twenty-six of the publications were off-topic. Quantitative data was only available for potential dermal exposure (surface contamination levels). Table 1 summarizes the results of the retrieved publications containing quantitative data.

On surfaces in the hospital pharmacy, drug administration areas, patient care areas and operation rooms, contaminations usually occurred within a range of a few pg/cm2 up to 200 ng/cm2. Mean and median concentrations were usually below 17.4 ng/cm2. Higher surface contaminations of up to 270 μg/cm2 were only reported by Viegas et al. (2014 and 2018) and Touzin et al. (2010). Viegas et al. (2014 and 2018) documented inadequate cleaning protocols and incorrect working procedures. Touzin et al. (2010) reported on the unsatisfying cleaning efficacy of a new cleaning protocol. It can therefore be concluded, that contamination of surfaces with hazardous drug in modern healthcare facilities usually does not exceed concentrations of 200 ng/cm2. Mean and median surface contaminations are considerably lower (few pg/cm2 up to 17.4 ng/cm2).

Quantifying the exposure of health workers to genotoxic drugs

Considering the results of our short review, we identified the dermal exposure as the major contributor to the total exposure of health workers to hazardous drugs. Few attempts to quantify and assess the dermal exposure of surface contaminants at the workplace have been made so far. A major obstacle in quantifying the dermal exposure is the limited knowledge on the transfer rates of (drug) molecules across the skin barrier. Conservative models therefore rely on the assumption that 100% of the applied substances are incorporated. Considering these limitations, Kimmel and co-workers developed a simple but useful model to quantify the contribution of dermal exposure to the total uptake of hazardous drugs at workplaces in the pharmaceutical industry [13]. A worst-case scenario assumes, that the daily dermal exposure equals the amount of substance on a surface area of 200 cm2 (skin area of both palms). Using the simple yet very conservative model of Kimmel et al. (2011) the daily dermal intake (DDI) of hazardous drugs can be derived using the following formula:

$$ DDI\ \left(\mu g/ day\right)=\frac\left(^2\right)\times SC\ \left(\mu g/^2\right)}} $$

(3)

With DDI = Daily dermal intake (μg/day)

SAEx = Exposed skin area (set to 200 cm2 by default)

SC = Surface contamination (μg/cm2)

AFBio = Adjustment factor bioavailability (100% = 1)

Considering the highest mean surface contamination value reported in the reviewed studies (17.4 ng/cm2, see Table 1), the mean DDI of health workers may be estimated to be below 3500 ng/day (3.5 μg/day) and the thereby below the previously proposed ADI of 4 μg/day.

Proposal of an acceptable surface contamination level and risk assessment

In “Using the TTC concept to define acceptable levels of exposures to genotoxic drugs in healthcare settings” section of this paper, we used a modified TTC-approach to estimate an acceptable daily intake (ADI) of genotoxic drugs of 4 μg/day that would not increase the risk of health workers suffering from work related cancer by 1 excess case in 100.000 workers following lifetime exposure (40 years). We subsequently identified the dermal contact to be the major route of exposure and derived the daily dermal uptake (DDI) as indicator of the total drug uptake (see “Occupational exposure to hazardous drugs in healthcare settings” section). Hence, safe working conditions can be assumed if

Since the DDI is only influenced by the extent of contamination of the surface getting in contact with the workers skin and the ADI is fixed to 4000 ng/day, an acceptable surface contamination level (ASCL) of 20 ng/cm2 may be derived as follows:

$$ ASCL\ \left(\frac\right)=\frac\right)}\ \left(200\frac\right)}=20\ ng/^2 $$

(4)

With

ASCL = Acceptable surface contamination level (ng/cm2)

ADI = Acceptable daily intake

SAEx = Exposed skin area (set to 200 cm2 by default)

The ASCL may serve as a conservative threshold of no concern for surface contaminations to protect health workers from suffering work related cancer.

The results of the review (see Table 1) show, that health workers usually do not get in contact with surfaces, that are contaminated above the aforementioned ASCL of 20 ng/cm2. Peak exposures may occur, if concentrated drug solutions are spilled in larger amounts and get in contact with the unprotected skin. Such exposures occur only accidental and are limited to a few lifetime events. They are unlikely to have a disproportionate effect on systemic concentrations that would significantly increase the lifetime (dermal) drug intake of health workers. It can therefore be concluded, that following modern drug handling guidelines, health works are not at risk of developing work related cancer due to occupational exposure to hazardous (genotoxic) drugs.