2-Year animal carcinogenicity results for crisaborole, a novel phosphodiesterase 4 inhibitor for atopic dermatitis.

BACKGROUND: Crisaborole is a novel, topical nonsteroidal, anti-inflammatory, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild to moderate atopic dermatitis. OBJECTIVE: As part of a nonclinical safety testing program, these 2-year studies tested the carcinogenic potential of crisaborole. METHODS: Crisaborole ointment, 2%, 5%, or 7%, was applied once daily topically to mice, and crisaborole was administered orally to rats at doses of 30, 100, or 300mg/kg/day for up to 104 weeks. Systemic exposure to crisaborole and its metabolites, moribundity/death, clinical signs, and tumor formation were assessed in each study. RESULTS: Crisaborole treatment was not tumorigenic in mice at any of the doses administered and did not increase the incidence of neoplastic or nonneoplastic microscopic lesions compared with controls. Oral administration of crisaborole at the high dose (300mg/kg/day) to female rats increased the incidence of treatment-related benign granular cell tumors in the distal reproductive tract (uterus with cervix and vagina) but did not cause moribundity/death. CONCLUSION: Crisaborole was well tolerated and not tumorigenic in mice. It was not tumorigenic in male rats at 300mg/kg/day at exposures that were 3× the human area under the concentration-time curve (AUC24) and was nontumorigenic in female rats at 100mg/kg/day at exposures that were 1× the human AUC24.

Systematic review of the association between oil and natural gas extraction processes and human reproduction.

This systematic review identified 45 original published research articles related to oil and gas extraction activities and human reproductive endpoints. Reproductive outcomes were categorized as [1] birth outcomes associated with maternal exposure, [2] semen quality, fertility, and birth outcomes associated with adult paternal exposure, [3] reproductive cancers, and [4] disruption of human sex steroid hormone receptors. The results indicate there is moderate evidence for an increased risk of preterm birth, miscarriage, birth defects, decreased semen quality, and prostate cancer. The quality of the evidence is low and/or inadequate for stillbirth, sex ratio, and birth outcomes associated with paternal exposure, and testicular cancer, female reproductive tract cancers, and breast cancer, and the evidence is inconsistent for an increased risk of low birth weight; therefore, no conclusions can be drawn for these health effects. There is ample evidence for disruption of the estrogen, androgen, and progesterone receptors by oil and gas chemicals, which provides a mechanistic rationale for how exposure to oil and gas activities may increase the health risks we have outlined. The results from this systematic review suggest there is a negative impact on human reproduction from exposure to oil and gas activities. Many of the 45 studies reviewed identified potential human health effects. Most of these studies focused on conventional oil and gas activities. Few studies have been conducted to evaluate the impact of unconventional oil and gas operations on human health. The impact of unconventional oil and gas activities may be greater than that of conventional activity, given that unconventional activities employ many of the same approaches and use dozens of known endocrine-disrupting chemicals in hydraulic fracturing.

[Influence of adjuvant hormonal therapy on the whole female organism: benefit versus potential injury]. / Einfluss einer adjuvanten Hormontherapie aud den Gesamtorganismus der Frau: Nutzen versus potentieller Schaden.

Not only do patients suffering from hormone receptor-positive tumors of the mammary gland show an increased survival rate, but patients with endometrial as well as ovarian cancer also benefit from hormone replacement therapy. On the one hand, hormonal treatment as well as any other medical treatment influences the tumor, and on the other hand it influences the whole body, which sometimes leads to unfavorable events (increased rate of endometrial cancers during tamoxifen therapy vs. increase of bone density in postmenopausal women). Therefore, hormonal cancer treatment is often suspect. As unfavorable events are rare, and since the benefit is convincing, doctors have to inform women about all the pros and cons of this treatment option, which leads to well-informed and cooperative patients.

Multigenerational effects of dietary fat carcinogenesis in mice.

The possibility of multigenerational transmission of a carcinogenic effect from exposure to a maternal diet high in fat was tested in mice. Diets with 2.6 or 29% fat (by weight) were fed to strain CD-1 mice during pregnancy. The female offspring were raised on a control diet (10% fat), mated, and continued on the control diet through pregnancy. Their female offspring were raised to terminal illness and autopsied. The total number of reproductive system tumors, pituitary tumors, and metastases was increased in the offspring with ancestral exposure to high dietary fat but to a lesser extent than had been reported previously for direct prenatal exposure to high maternal dietary fat. Because previous work has given evidence against germ cell transmission, a hypothesis based on a maternal effect was offered to explain the multigenerational carcinogenesis. These results have implications for epidemiological studies.