A new database contains 520 studies investigating the carcinogenicity data of 238 pharmaceuticals across 14 ATC classifications

Recently, we provided a new database with toxicity data from non-clinical animal studies along with human information for 528 approved drugs [1]. The database contains non-clinical studies for repeat-dose, carcinogenicity, developmental toxicity, and reproductive toxicity. It is made available free of charge at https://iuclid6.echa.europa.eu/us-fda-toxicity-data. The terminology used within this database has been harmonized to support further analyses, such as correlation and concordance studies. The corresponding ontology is accessible at https://github.com/innovamol/PaCCO. The database can be used for correlation and concordance analyses [2], as well as offering insights into the tumorigenic potential of structural analogues [3] by including structural information from other sources because the database does only contain identifiers such as international nonproprietary name. It facilitates the examination of species and strain sensitivities and aids in the adoption of new approach methodologies (NAMs) [4,5] in alignment with regulatory standards [6].In this research brief, our goal is to enhance data presentation for practical usage within the cancer research community. To support this, the carcinogenicity study information has been made available as Excel file (Supplementary Material).The database [1] contains 520 studies investigating the tumorigenic potential of 241 pharmaceuticals, meaning a density of approximately two studies per drug. This finding is in line with the regulatory requirement to test in two species, usually rat and mouse.The database includes approved medical drugs of 14 ATC classifications (Figure 1): 46 drugs targeting the alimentary tract and metabolism (100 studies), 18 anti-infectives for systemic use (30 studies), 28 anti-neoplastic and immunomodulating agents (52 studies), 2 antiparasitic products (5 studies), 15 drugs targeting blood and blood forming organs (27 studies), 25 cardiovascular drugs (64 studies), 5 dermatologicals (15 studies), 16 drugs targeting the genitourinary system and sex hormones (32 studies), 6 drugs acting on the musculo-skeletal system (13 studies), 50 drugs targeting the nervous system (118 studies), 12 drugs acting on the respiratory system (24 studies), 4 drugs targeting the sensory system (14 studies), 8 systemic hormonal preparations excluding sex hormones and insulins (14 studies), and 3 various drugs (6 studies).Tumorigenic potential was primarily investigated in two species: 253 studies using mice and 263 studies using rats. The Chinese hamster was used in only one study, and the New Zealand White rabbit in another.The following mouse strains were used in the indicated percentages of mouse studies: CD-1 (ca 60%), B6C3F1 (ca 10%), CB6F1 (ca 5%), other Tg (ca 4%), and NMRI (ca 4%). Other strains used in a very few studies included C57BL, SWISS, Balb/c, ICR, and specific knockout strains. In around 8% of studies, the mouse strain was not specified.Of the 263 rat studies, 56% were conducted with Sprague-Dawley, 22% with Wistar, and 5% with Fischer 344 rats. A few other studies were performed with other albino rat strains or Long Evans rats in two studies. In approximately 7% of studies the rat strain was not specified.The distribution of species and strains in the carcinogenicity studies of our database is consistent with the use of mouse and rat strains typically encountered when testing for tumorigenic potential for regulatory needs [7].Figure 2 illustrates the sex specificity of tumours targeting specific organs/tissues across the predominantly used mouse and rat strains. The figure was constructed by filtering the provided dataset so that the basis for effect corresponds to neoplastic histopathological findings, in rats or mice, and for which the sex for which the effect was reported has been provided. We then identified the two most common strains for each species and mapped all other strains to "other".For each species and strain combination we counted the number of studies for the eight most common effects after mapping the ontology. Table 1 provides a detailed analysis, showing the incidence of various tumours by sex: in males only, females only, or in both sexes. It is important to note that not all studies were conducted in both sexes, and this is noted to ensure transparency regarding the scope of our data and to help set realistic expectations for its use.Figure 3 shows the ontology terms associated with the effect levels plotted in Figure 2. We note that the same ontology term can have different hierarchy in the ontology, in which case it is shown only once. In the genitourinary system, 7 pharmaceuticals showed tumorigenic potential in the kidneys (2 in males only, 4 in both sexes, and 1 in females only). Regarding hepatobiliary organs and tissues, in the liver, 59 pharmaceuticals induced tumour growth (17 in males only, 27 in both sexes, 15 in females only).In reproductive and endocrine organs/tissues, 26 drugs impacted the adrenal glands (9 in males only, 10 in both sexes, 7 in females only), while 27 influenced mammary tissues (none in males only, 4 in both sexes, 23 in females only). In addition, 44 substances affected the thyroid/parathyroid (17 in males only, 21 in both sexes, and 6 in females only), with parathyroid effects observed in 11 substances (2 in males only and 9 in both sexes). Tumours also developed in the ovaries (15 substances) and the uterus (16 substances). The pituitary was affected by 32 pharmaceuticals (4 in males only, 17 in both sexes, 11 in females only), and 31 substances impacted the testes. Thyroid figures are provided above. For the immune system, 21 pharmaceuticals promoted growth in lymphatic tissues (3 in males only, 12 in both sexes, 6 in females only), and 7 affected the thymus (1 in males only, 2 in both sexes, 4 in females only). Table 1 includes additional numerical data on pharmaceuticals with tumorigenic potential affecting blood constituents, blood-forming tissues, bone, connective tissues, intestine, lungs, pancreas, skin, stomach, and urinary bladder.For 23 NDAs, tumorigenic potential in rat thyroid glands (hyperplasia, adenoma, and/or carcinoma) was observed in conjunction with liver effects (e.g., increased liver weight, liver hypertrophy, and/or hyperplasia). This finding aligns with the established understanding that neoplastic changes in the thyroid of rodents can occur as a secondary consequence of liver effects altering the metabolism of thyroid hormones [8].Our database [1] includes information from repeat-dose toxicity studies, which are valuable for identifying potential concerns regarding tumorigenic potential (only available in the original source files which are attached to the IUCLID dossiers of the database [1,9]; IUCLID stands for International Uniform ChemicaL Information Database [10]). The distribution of species and strains in our database does not necessarily reflect ICH guidance (S1B) [11], as many data are linked to experimental studies performed before these guidelines were established. However, it is important to consider these guidelines as published by the EMA can also be effectively used for comparison and context [11]. Indeed, sub-acute, sub-chronic and chronic repeat-dose toxicity studies reveal morphological changes, such as the presence of poorly differentiated or undifferentiated cells and hyperplasia in tissues and organs, signalling potential carcinogenic concerns. Moreover, these studies contribute to a weight of evidence approach, supporting conclusions about tumorigenic potential.For example, our database lists 679 'hyperplasia' events in different organs and tissues (for example, adrenal glands, bone marrow, gastric glands, mammary glands, liver, thymus, etc.) among 65,403 reported effects across the 2,270 oral repeat-dose toxicity studies [1]. Another valuable example can be represented by liver and thyroid tumorigenesis data. The database reports 581 liver effects (e.g. increased liver weight, enlarged liver, liver inflammation, abnormal liver morphology) and 184 thyroid effects (e.g. thyroid gland hyperplasia, thyroid carcinoma, thyroid follicular adenoma). All carcinogenicity studies on more than 50 compounds found a total of 3,365 effects in the ATC class connected to the nervous system, which is one of the most represented categories. Out of these, 93 individual effects are classified as histopathology neoplastic (duplicates excluded). The most common type of tumour found is hepatocellular adenoma.The carcinogenicity study information is available in Excel form as Supplementary Material. The dataset has been created by extracting the pre-clinical carcinogenicity study information from the IUCLID dossiers [1,8]