Mammalian spermatogenesis requires a stem cell pool, a period of amplification of cell numbers, the completion of reduction division to haploid cells (meiosis), and the morphological transformation of the haploid cells into spermatozoa (spermiogenesis). The net result of these processes is the production of massive numbers of spermatozoa over the reproductive lifetime of the animal. One study that utilized homogenization-resistant spermatids as the standard determined that human daily sperm production (dsp) was at 45 million per day per testis (60). For each human that means ∼1,000 sperm are produced per second. A key to this level of gamete production is the organization and architecture of the mammalian testes that results in continuous sperm production. The seemingly complex repetitious relationship of cells termed the "cycle of the seminiferous epithelium" is driven by the continuous commitment of undifferentiated spermatogonia to meiosis and the period of time required to form spermatozoa. This commitment termed the A to A1 transition requires the action of retinoic acid (RA) on the undifferentiated spermatogonia or prospermatogonia. In stages VII to IX of the cycle of the seminiferous epithelium, Sertoli cells and germ cells are influenced by pulses of RA. These pulses of RA move along the seminiferous tubules coincident with the spermatogenic wave, presumably undergoing constant synthesis and degradation. The RA pulse then serves as a trigger to commit undifferentiated progenitor cells to the rigidly timed pathway into meiosis and spermatid differentiation.

Spermatogenesis: The Commitment to Meiosis

Safety assessment on polyethylene glycols (PEGs) and their derivatives as used in cosmetic products

Silastic tubing containing cyproterone acetate or braided silk sutures impregnated with WIN18446 or ORF-1616 were inserted under the tunica albuginea of the testes. Spermatogenesis was suppressed in tubules in the immediate vicinity of the implants, but the interstitial tissue associated with the atrophic tubules appeared more abundant. Electron micrographs showed hypertrophy of the smooth endoplasmic reticulum and other evidence of Leydig cell stimulation. Interstitial tissue in the same testis at a distance from the implants showed no evidence of stimulation. The results are discussed in relation to the possibility of a local feedback from the tubules modulating sensitivity of the Leydig cells to circulating gonadotropin.

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Is there a local feedback from the seminiferous tubules affecting activity of the Leydig cells

Gadolinium chelates, intended as intravenous contrast media for magnetic resonance imaging, have been regarded as nonnephrotoxic and recommended to replace iodinated contrast media in patients with azotemia who are undergoing digital subtraction angiography (DSA). High intraarterial doses (up to 220 mmol of gadodiamide) have been used, with a 40% incidence of nephropathy. The authors discourage the use of gadolinium for DSA for several reasons. (a) There exist no randomized studies comparing the nephrotoxic effects of gadolinium-based and iodinated media at equal-attenuating concentrations and doses. (b) Gadolinium-based media are hypertonic, a pathogenetic factor in contrast medium-induced nephropathy after renal angiography, with an osmolality two to seven times that of plasma. Iodinated media in concentrations that are equally attenuating with gadolinium-based media can be made isotonic. (c) In vitro measurements indicate that 0.5 mol/L gadolinium chelates are equally attenuating with 60-80 mg iodine per milliliter at the commonly used 70-90-kV range used for DSA. Thus, 50 mL of 0.5 mol/L gadolinium chelate ( approximately 0.3 mmol/kg in an 80-kg person) would be equally attenuating with a dose of 3-4 g of iodine in an iodinated medium (eg, 50 mL iohexol at 60-80 mg I/mL or 10-13 mL at 300 mg I/mL). (d) By combining these data on attenuation and results of toxicity studies in mice, the general toxicity of gadolinium chelates may be six to 25 times higher than that of equal-attenuating doses of iodinated media at 70-kV DSA. Thus, the authors believe that at equal-attenuating doses for DSA, modern iodinated contrast media should result in a lower toxic load on the body than with presently available gadolinium chelates.

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Are gadolinium-based contrast media really safer than iodinated media for digital subtraction angiography in patients with azotemia?

The cosmetic ingredient Zinc Pyrithione (ZPT) (CAS No 13463-41-7, EC No 236-671-3) with the chemical name Bis[(2-pyridyl-1-oxo)-thio]zinc is currently regulated as a preservative in rinse-off products (excluding oral hygiene products) in a concentration up to 0.5% in general and up to 1.0% in hair products (Annex V/8). Furthermore, ZPT is also allowed in a concentration up to 0.1% in leave-on hair products (Annex Ш/101).

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Scientific Committee on Consumer Safety SCCS

7-Chloro-4-indanol in concentrations of 1:1,000–1:3,000 is rapidly lethal to vegetative bacteria, Trichophyton sp., C. albicans, E. histolytica cysts and trophozoites, T. vaginalis , and spermatozoa in vitro . Systemic toxicity is low; it is well tolerated by skin, eyes, genital mucosa; it is nonallergenic; it appears to be suitable for use as. topical antiseptic or sanitizer.

The Biological Properties of Chlorindanol, A New Antiseptic Agent*

The biologic actions of a new series of bis(dichloroacetyl) diamines.

N,N′-4-Xylylene-bis(N-ethyldichloroacetamide), Compound I,and N,N′-bis (dichloroacetyl)-l,8-octamethylenediamine, Compound II, produced in rats marked testicular weight regression associated with complete arrest of spermatogenesis. Compound II was approximately eight times more active, per mg., than Compound I. At maximal effects the seminiferous tubules consisted merely of a ring of Sertoli cells with spermatogonia interspersed. Leydig cell morphology and androgen production were not altered by antispermatogenic doses of either agent. The weight of the adrenal glands was lowered by high doses of both compounds although the adrenals appeared normal histologically. The plasma corticosterone level of chronically medicated rats was not different from that of control animals. Also, the rise in plasma corticosterone concentration observed two hours after ACTH administration was not altered by prior medication with Compound II. Concurrent injections of 10 r.u. per rat per day of commercial pituitary gonadotroph...

The selective testicular effects of certain bis-(dichloroacetyl) diamines

Inhibition and recovery of spermatogenesis in rats, monkeys, and dogs medicated with bis(dichloroacetyl)diamines.

Observations on the acute intravenous toxicity of a series of 3, 5-diacylamino-2,4,6-triiodobenzoic acids in mice were presented. The least toxic compound of this series was found to be sodium 3,5-diacetamido-2,4,6-triiodobenzoate, sodium diatrizoate.

The most striking property of sodium diatrizoate was its uniformly low systemic toxicity in various animal species. Acute intravenous LD50 values from 11.3 to 14 gm./kgm. were obtained in the mouse, rat, rabbit, cat and dog.

Dose-mortality curves were sharply defined in each of the animal species. At lethal dose levels, death occurred in a few minutes to 2 to 3 hours as a result of massive breakdown of the pulmonary circulation and consequent right heart failure.

Local tissue toxicity was found to be low as judged by the absence of intimal injury upon repeated intravenous injection of a 50 per cent solution of sodium diatrizoate into the marginal ear vein of the rabbit.

No obvious evidence of pharmacodynamic activity in the cat and dog was observed at intravenous doses of 0.5 to 2.0 gm./kgm.

Sodium diatrizoate was well tolerated by rats when given intravenously in five consecutive daily dosages of 0.5 and 2.0 gm./kgm. One death was observed at 4 gm./kgm. with renal tubular nephrosis occurring in five of nine rats at this dose level.

Sodium diatrizoate was well tolerated without mortality or effect on body weight in monkeys at three successive dosages of 0.5, 1.0 and 2.0 gm./kgm. No significant histologic changes were observed.

Comparative acute toxicity data on several urographic contrast media in the mouse and rat were presented.

Observations on the toxicity of a new urographic contrast medium, sodium 3, 5-diacetamido-2, 4, 6-triiodobenzoate (hypaquesodium) and related compounds.

Frederick Coulston

Papers

The Biological Properties of Chlorindanol, A New Antiseptic Agent*

The biologic actions of a new series of bis(dichloroacetyl) diamines.

The selective testicular effects of certain bis-(dichloroacetyl) diamines

Inhibition and recovery of spermatogenesis in rats, monkeys, and dogs medicated with bis(dichloroacetyl)diamines.

Observations on the toxicity of a new urographic contrast medium, sodium 3, 5-diacetamido-2, 4, 6-triiodobenzoate (hypaquesodium) and related compounds.